CN101142228A - Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity - Google Patents

Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity Download PDF

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CN101142228A
CN101142228A CNA2005800491411A CN200580049141A CN101142228A CN 101142228 A CN101142228 A CN 101142228A CN A2005800491411 A CNA2005800491411 A CN A2005800491411A CN 200580049141 A CN200580049141 A CN 200580049141A CN 101142228 A CN101142228 A CN 101142228A
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alkyl group
low
low alkyl
chr
grade alkenyl
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S·J·德马科
K·默勒
H·亨策
O·塞利耶
F·荣格
F·贡贝特
D·奥伯莱希特
C·卢丁
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Universitaet Zuerich
Spexis AG
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Universitaet Zuerich
Polyphor AG
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Priority to CN201510320667.4A priority Critical patent/CN105111280B/en
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Priority to HK16101770.6A priority patent/HK1213914A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

The present invention provides a beta-hairpin peptide mimetics fixed by the mould plate of general formula (I) or the salt thereof, wherein, Z is the chain of the eleven alpha-amino acid residues, these residues are Gly or Pro or Pro(4NHCOPhe) according to the position (count from the N-end amino acid) of these residues in the chain, or has some kinds defined in the instruction book and the claim, other symbols in the upper formula are defined in the instruction book or claim, and they comprises the properties of inhibiting protease (in particular the serine proteinase, especially the cathepsin G or elastase or tryptase). These beta-hairpin peptide mimetics can be produced with the method basing on the strategy of mixing the solid phase with the liquid phase to synthesize.

Description

Template fixed β-hairpin peptidomimetics with protease inhibiting activity
The invention provides template fixed β-hairpin peptidomimetics, it template that comprises 11 a-amino acid residues is chain fixedly, and these residues are summarized, and their positions in chain are Gly or Pro or Pro (4NHCOPhe), or has hereinafter some kind of definition.The inhibitor of these template fixed β-hairpin peptidomimetics useful as protease.They especially can be used as the inhibitor of different serine proteases (for example, human cathepsin g, elastoser or tryptase).In addition, the invention provides a kind of high-efficiency method, if necessary, can make these compounds with the library form by this method.
β-hairpin peptidomimetics of the present invention has shown the effectiveness, the oral administration biaavailability that improve, the transformation period of improving, and most important ground, highly selective rate between different serine proteases, this depends on the suitable selection to some type of a-amino acid residue, and their positions in described chain.In addition, these β-hairpin peptidomimetics have shown for erythrocytic low hemolytic action and low cytotoxicity.
To showing promising therepic use in the treatment of diseases, described disease is cancer (R.P.Beckett, A.Davidson, A.H.Drummond, M.Whittaker, Drug Disc.Today 1996,1,16-26 for example for the inhibitor of proteolytic enzyme; L.L.Johnson, R.Dyer, D.J.Hupe, Curr.Opin.Chem.Biol.1998,2,466-71; D.Leung, G.Abbenante, and D.P.Fairlie, J.Med.Chem.2000,43,305-341, T.Rockway, Expert Opin.Ther.Patents 2003,13,773-786), parasite, fungi and virus infection [schistosomicide (M.M.Becker, S.A.Harrop, J.P.Dalton for example, B.H.Kalinna, D.P.McManus, D.P.Brindley, J.Biol.Chem.1995,270,24496-501); C.albicans (C.Abad-Zapetero, R.Goldman, S.W.Muchmore, C.Hutchins, K.Stewart, J.Navaza, C.D.Payne, T.L.Ray, Protein Sci.1996,5,640-52), HIV (A.Wlodawer, J.W.Erickson, Annu.Rev.Biochem.1993,62,543-85; P.L.Darke, J.R.Huff, Adv.Pharmacol.1994,5,399-454), hepatitis (J.L.Kim, K.A.Morgenstern,, C.Lin, T.Fox, M.D.Dwyer, J.A.Landro, S.P.Chambers, W.Markland, C.A.Lepre, E.T.O ' Malley, S.L.Harbeson, C.M.Rice, M.A.Murcko, P.R.Caron, J.A.Thomson, Cell, 1996,87,343-55; R.A.Love, H.E.Parge, J.A.Wickersham, Z.Hostomsky, N.Habuka, E.W.Moomaw, T.Adachi, Z.Hostomska, Cell, 1996,87,331-342), bleb (W.Gibson, M.R.Hall, Drug.Des.Discov.1997,15,39-47)] and inflammatory, immunity, respiratory disease (P.R.Bernstein, P.D.Edwards, J.C.Williams, Prog.Med.Chem.1994,31,59-120; T.E.Hugli, Trends Biotechnol.1996,14,409-12), cardiovascular disorder (M.T.Stubbs, W.A.Bode, Thromb.Res.1993,69,1-58; H.Fukami et al, Current Pharmaceutical Design 1998,4 is 439-453) with the neurodegeneration defective, comprise alzheimer's disease (R.Vassar, B.D.Bennett, S.Babu-Kahn, S.Kahn, E.A.Mendiaz, Science, 1999,286,735-41), (people such as Kaatinen M takes place in blood vessel, Atherosklerosis 1996,1231-2,123-131) and multiple sclerosis (people such as Ibrahim MZ, J.Neuroimmunol 1996,70,131-138.
Because most of proteolytic enzyme with they substrate with extend or the beta chain conformation combine, therefore good inhibitor must can be simulated this conformation.Thereby, say that ideally β-hair clip stand-in are fit to pin peptide sequence with the conformation of extending.
In proteolytic enzyme, serine protease has constituted important treatment target.By its substrate specificity (the particularly residue type of P1 position discovery), serine protease is categorized as: (is preferred at the residue Lys/Arg of P1 bit strip positive charge) of trypsin-like, (the P1 position is little hydrophobic residue Ala/Val) of elastoser sample or chymotrypsin-like (is big hydrophobic residue Phe/Tyr/Leu in the P1 position).Can the PDB database (PDB: Www.rcsb.org/pdb) those serine proteases of go up obtaining its proteinase inhibitor X ray crystal data comprise trypsinase, alpha-chymotrypsin, γ-Quimotrase, people's neutrophilic granulocyte elastoser, zymoplasm, subtilisin, human cytomegalic inclusion disease virus, protease A, achromobacter (achromobacter), human cathepsin g, glutamate specific proteolytic enzyme, carboxypeptidase D, proconvertin a, pig thrombin 1XA, mesentery (mesenterico) peptase, HCV proteolytic enzyme and hot enzyme (thermitase).Other serine protease with treatment benefit comprises tryptase, complement saccharase, hepatitis C-NS3 proteolytic enzyme.Zymoplasm (J.L.Metha for example, L.Y.Chen, W.W.Nichols, C.Mattsson, D.Gustaffson, T.G.P.Saldeen, J.Cardiovasc.Pharmacol.1998,31,345-51; C.Lila, P.Gloanec, L.Cadet, Y.Herve, J.Fournier, F.Leborgne, T.J.Verbeuren, G.DeNanteuil, Synth.Comm.1998,28,4419-29) and factor Xa (J.P.Vacca for example, Annu.Rep.Med.Chem.1998,33, inhibitor 81-90) just is being used as anti-coagulant in clinical assessment, the inhibitor of elastoser (J.R.Williams, R.C.Falcone, C.Knee, R.L.Stein, A.M.Strimpler, B.Reaves, R.E.Giles, R.D.Krell, Am.Rev.Respir.Dis.1991,144,875-83) be in the clinical trial at pulmonary emphysema and other pulmonary disorder, and tryptase inhibitors is in (C.Seife in the phase ii clinical trial at asthma at present, Science1997,277,1602-3), urokinase inhibitors is used for mammary cancer, and chymase inhibitor is used for cardiac-related diseases.At last, cathepsin G and elastoser participate in the active adjusting of cytokine and acceptor thereof closely.Particularly on the position of inflammation, the wetting property polymorphonuclear cell that has tight temporal correlation from the level with the inflammatory cytokine rising discharges cathepsin G, elastoser and protease 3, this shows strongly, these proteolytic enzyme participate in the control (U.Bank of pair cell factor biological activity and availability, S.Ansorge, J.Leukoc.Biol.2001,69,177-90).Therefore, the inhibitor of elastoser and cathepsin G constituted the new drug material standed for that is used in particular for chronic obstructive disease of lung valuable target (Ohbayashi H, Epert Opin.Investig.Drugs 2002,11,965-980).
In the multiple proteins sex pilus propylhomoserin proteinase inhibitor that exists, a kind of is 14 amino acid whose cyclic peptides, and it is from sunflower seed, be called as Sunflower Receptacle trypsin inhibitor (SFTI-1) (S.Luckett, R.Santiago Garcia, J.J.Barker, A.V.Konarev, P.R.Shewry, A.R.Clarke, R.L.Brady, J.Mol.Biol.1999,290,525-533; Y.-Q.Long, S.-L.Lee, C.-Y.Lin, I.J.Enyedy, S.Wang, P.Li, R.B.Dickson, P.P.Roller, Biorg.﹠amp; Med.Chem.Lett.2001,11,2515-2519), its demonstration and the reactive similarity that has on sequence and the conformation of encircling of the trypsinase of the serpin of Bowman-Birk family.This inhibitor adopts β-hair clip conformation with ox β-tryptic avtive spot when combining.SFTI-1 suppresses β-trypsin K i＜0.1nM), (K of cathepsin G i～0.15nM), elastoser (K i～105 μ M), Quimotrase (K i～7.4 μ M) and zymoplasm (K i～136mM).
We are in these means that inhibitor design is described for example, and it comprises and will be transplanted on the template of inducing hair clip from the beta-hairpin loop of naturally occurring peptide.Based on the 3D structure of the β that fully defines-hair clip stand-in, can design library of compounds, this finally causes demonstrating the inhibitor that has the novelty of different specific characteristics for some proteinoid enzymes.
At document (D, Obrecht, M.Altorfer, J.A.Robinson, Adv.Med.Chem.1999,4,1-68; J.A.Robinson, Syn.Lett.2000,4, described and template bonded hair clip simulating peptide in 429-441), at International Patent Application WO 2003/054000 A1 and Descours A, Moehle K., Renard A, Robinson J.ChemBio Chem 2002,3, described template fixed peptide analogue that suppresses serine protease and the method for synthesizing them among the 318-323, but previously disclosed these molecules do not show highly selective and extra high effectiveness.Yet, set up now the ability of using combination and parallel synthetic method to produce β-hairpin peptidomimetics (L.Jiang, K.Moehle, B.Dhanapal, D.Obrecht, J.A.Robinson, Helv.Chim.Acta.2000,83,3097-3112).
Aforesaid method allows synthetic and screens big hair clip stand-in library, this so promoted structure-activity research to a great extent, and promoted thus to have highly effectively and optionally serine protease suppress activity, oral administration biaavailability, to the low hemolytic activity of HRBC and low Cytotoxic recruit's discovery.
β-hairpin peptidomimetics of the present invention is the compound of following general formula, and their pharmacy acceptable salt,
Wherein
Figure A20058004914100742
Be the group of one of following formula:
Figure A20058004914100751
Figure A20058004914100761
Wherein,
Figure A20058004914100762
Be Gly, or the residue of L-a-amino acid, wherein B is formula-NR 20CH (R 71)-residue, or the enantiomer of one of A1 to the A69 group of definition hereinafter;
Figure A20058004914100763
Be the group of one of following formula:
Figure A20058004914100764
Figure A20058004914100771
Figure A20058004914100791
R 1Be H, low alkyl group or aryl lower alkyl;
R 2Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 3Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 4Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 5Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 6Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CH 61) sC 6H 4R 8
R 7Be alkyl, thiazolinyl ,-(CH 2) q(CHR 61) sOR 55,-(CH 2) q(CHR 61) sNR 33R 34,-(CH 2) q(CHR 61) sOCONR 33R 75,-(CH 2) q(CHR 61) sNR 33R 82,-(CH 2) r(CHR 61) sCOOR 57,-(CH 2) r(CHR 61) sCONR 58R 59,-(CH 2) r(CHR 61) sPO (OR 60) 2,-(CH 2) r(CHR 61) sSO 2R 62Or-(CH 2) r(CHR 61) sC 6H 4R 8
R 8Be H, Cl, F, CF 3, NO 2, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) NR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sCOR 64
R 9Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 10Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 11Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 12Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) r(CHR 61) sCOOR 57,-(CH 2) r(CHR 61) sCONR 58R 59,-(CH 2) r(CHR 61) sPO (OR 60) 2,-(CH 2) r(CHR 61) sSO 2R 62Or-(CH 2) r(CHR 61) sC 6H 4R 8
R 13Be alkyl, thiazolinyl ,-(CH 2) q(CHR 61) sOR 55,-(CH 2) q(CHR 61) sSR 56,-(CH 2) q(CHR 61) sNR 33R 34,-(CH 2) q(CHR 61) sOCONR 33R 75,-(CH 2) q(CHR 61) sNR 20CONR 33R 82,-(CH 2) q(CHR 61) sCOOR 57,-(CH 2) q(CHR 61) sCONR 58R 59,-(CH 2) q(CHR 61) sPO (OR 60) 2,-(CH 2) q(CHR 61) sSO 2R 62Or-(CH 2) q(CHR 61) sC 6H 4R 8
R 14Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) q(CHR 61) sCOOR 57,-(CH 2) q(CHR 61) sCONR 58R 59,-(CH 2) q(CHR 61) sPO (OR 60) 2,-(CH 2) q(CHR 61) sSOR 62Or-(CH 2) q(CHR 61) sC 6H 4R 8
R 15Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 16Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 17Be alkyl, thiazolinyl ,-(CH 2) q(CHR 61) sOR 55,-(CH 2) q(CHR 61) sSR 56,-(CH 2) q(CHR 61) sNR 33R 34,-(CH 2) q(CHR 61) sOCONR 33R 75,-(CH 2) q(CHR 61) sNR 20CONR 33R 82,-(CH 2) q(CHR 61) sCOOR 57,-(CH 2) q(CHR 61) sCONR 58R 59,-(CH 2)) q(CHR 61) sPO (OR 60) 2,-(CH 2) q(CHR 61) sSO 2R 62Or-(CH 2) q(CHR 61) sC 6H 4R 8
R 18Be alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sSR 56,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSOR 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 19Be low alkyl group ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sSR 56,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8Perhaps
R 18And R 19Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 20Be H, alkyl, thiazolinyl or aryl lower alkyl;
R 21Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSOR 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 22Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 23Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 24Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 32R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) oCHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 25Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 26Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o (CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8Perhaps
R 25And R 26Can form together :-(CH 2) 2-6,-(CH 2) rO (CH 2) r-,-(CH 2) rS (CH 2) r-or-(CH 2) rNR 57(CH 2) r-;
R 27Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 28Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) s-OR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 29Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61)) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 30Be H, alkyl, thiazolinyl or aryl lower alkyl.
R 31Be H, alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 32Be H, low alkyl group or aryl lower alkyl;
R 33Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 34R 63,-(CH 2) m(CHR 61) sOCONR 75R 82,-(CH 2) m(CHR 61) sNR 20CONR 78R 82,-(CH 2) o(CHR 61) sCOR 64,-(CH 2) o(CHR 61) s-CONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 34Be H, low alkyl group, aryl or aryl lower alkyl;
R 33And R 34Can form together :-(CH 2) 2-6,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 35Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) p(CHR 61) sC 6H 4R 8
R 36Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 37Be H, F, Br, Cl, NO 2, CF 3, low alkyl group ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 38Be H, F, Br, Cl, NO 2, CF 3, alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 39Be H, alkyl, thiazolinyl or aryl lower alkyl;
R 40Be H, alkyl, thiazolinyl or aryl lower alkyl;
R 41Be H, F, Br, Cl, NO 2, CF 3, alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 42Be H, F, Br, Cl, NO 2, CF 3, alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 43Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) p(CHR 61) sC 6H 4R 8
R 44Be alkyl, thiazolinyl ,-(CH 2) r(CHR 61) sOR 55,-(CH 2) r(CHR 61) sSR 56,-(CH 2) r(CHR 61) sNR 33R 34,-(CH 2) r(CHR 61) sOCONR 33R 75,-(CH 2) r(CHR 61) sNR 20CONR 33R 82,-(CH 2) r(CHR 61) sCOOR 57,-(CH 2) r(CHR 61) sCONR 58R 59,-(CH 2) r(CHR 61) sPO (OR 60) 2,-(CH 2) r(CHR 61) sSO 2R 62Or-(CH 2) r(CHR 61) sC 6H 4R 8
R 45Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) s(CHR 61) sCONR 58R 59,-(CH 2) s(CHR 61) sPO (OR 60) 2,-(CH 2) s(CHR 61) sSO 2R 62Or-(CH 2) s(CHR 61) sC 6H 4R 8
R 46Be H, alkyl, thiazolinyl or-(CH 2) o(CHR 61) pC 6H 4R 8
R 47Be H, alkyl, thiazolinyl or-(CH 2) o(CHR 61) sOR 55
R 48Be H, low alkyl group, low-grade alkenyl or aryl lower alkyl;
R 49Be H, alkyl, thiazolinyl ,-(CHR 61) sCOOR 57, (CHR 61) sCONR 58R 59, (CHR 61) sPO (OR 60) 2,-(CHR 61) sSOR 62Or-(CHR 61) sC 6H 4R 8
R 50Be H, low alkyl group or aryl lower alkyl;
R 51Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) pPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) p-(CHR 61) sC 6H 4R 8
R 52Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) pPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) p(CHR 61) sC 6H 4R 8
R 53Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) pPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) p(CHR 61) sC 6H 4R 8
R 54Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) COOR 57,-(CH 2) o(CHR 61) sCONR 58R 59Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 55Be H, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH 2) m(CHR 61) sOR 57,-(CH 2) m(CHR 61) sNR 34R 63,-(CH 2) m(CHR 61) sOCONR 75R 82,-(CH 2) m(CHR 61) sNR 20CONR 78R 82,-(CH 2) o(CHR 61) s-COR 64,-(CH 2) o(CHR 61) COOR 57Or-(CH 2) o(CHR 61) sCONR 58R 59
R 56Be H, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH 2) m(CHR 61) sOR 57,-(CH 2) m(CHR 61) sNR 34R 63,-(CH 2) m(CHR 61) sOCONR 75R 82,-(CH 2) m(CHR 61) sNR 20CONR 78R 82,-(CH 2) o(CHR 61) s-COR 64Or-(CH 2) o(CHR 61) sCONR 58R 59
R 57Be H, low alkyl group, low-grade alkenyl, aromatic yl elementary alkyl or heteroaryl low alkyl group;
R 58Be H, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl or heteroaryl-low alkyl group;
R 59Be H, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl or heteroaryl-low alkyl group; Perhaps
R 58And R 59Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 60Be H, low alkyl group, low-grade alkenyl, aryl or aryl lower alkyl;
R 61Be alkyl, thiazolinyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-low alkyl group ,-(CH 2) mOR 55,-(CH 2) mNR 33R 34,-(CH 2) mOCONR 75R 82,-(CH 2) mNR 20CONR 78R 82,-(CH 2) oCOOR 37,-(CH 2) oNR 58R 59Or-(CH 2) oPO (COR 60) 2
R 62Be low alkyl group, low-grade alkenyl, aryl, heteroaryl or aryl lower alkyl;
R 63Be H, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-low alkyl group ,-COR 64,-COOR 57,-CONR 58R 59,-SO 2R 62Or-PO (OR 60) 2
R 34And R 63Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 64Be H, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-low alkyl group ,-(CH 2) p(CHR 61) sOR 65,-(CH 2) p(CHR 61) sSR 66Or-(CH 2) p(CHR 61) sNR 34R 63,-(CH 2) P(CHR 61) sOCONR 75R 82,-(CH 2) P(CHR 61) sNR 20CONR 78R 82
R 65Be H, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl, heteroaryl-low alkyl group ,-COR 57,-COOR 57Or-CONR 58R 59
R 66Be H, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl, heteroaryl-low alkyl group or-CONR 58R 59
M is 2-4; O is 0-4; P is 1-4; Q is 0-2; R is 1 or 2; S is 0 or 1;
Z is the chain of 11 a-amino acid residues, the position of described amino-acid residue in described chain begins counting from-terminal amino acid, thus, depend on their positions in chain, these amino-acid residues are Gly, Pro, Pro (4NHCOPhe) or have formula-A-CO-, or have formula-B-CO-, perhaps have one of following type:
C：-NR 20CH(R 72)CO-；
D：-NR 20CH(R 73)CO-；
E：-NR 20CH(R 74)CO-；
F:-NR 20CH (R 84) CO-; And
H:-NR 20-CH (CO-)-(CH 2) 4-7-CH (CO-)-NR 20-,-NR 20-CH (CO-)-(CH 2) pSS (CH 2) p-CH (CO-)-NR 20-,-NR 20-CH (CO-)-((CH 2) pNR 20CO (CH 2) p-CH (CO-)-NR 20-and-NR 20-CH (CO-)-((CH 2) pNR 20CONR 20(CH 2) p-CH (CO-)-NR 20-;
R 71Be low alkyl group, low-grade alkenyl ,-(CH 2) p(CHR 61) sOR 75,-(CH 2) p(CHR 61) sSR 75,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 75,-(CH 2) pCONR 58R 59,-(CH 2) pPO (OR 62) 2,-(CH 2) pSO 2R 62Or-(CH 2) o-C 6R 67R 68R 69R 70R 76
R 72Be H, low alkyl group, low-grade alkenyl ,-(CH 2) p(CHR 61) sOR 85Or-(CH 2) p(CHR 61) sSR 85
R 73Be-(CR 86R 87) oR 77,-(CH 2) rO (CH 2) oR 77,-(CH 2) rS (CH 2) oR 77Or-(CH 2) rNR 20(CH 2) oR 77
R 75Be low alkyl group, low-grade alkenyl or aryl lower alkyl;
R 33And R 75Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 75And R 82Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 76Be H, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH 2) oOR 72,-(CH 2) oSR 72,-(CH 2) oNR 33R 34,-(CH 2) oOCONR 33R 75,-(CH 2) oNR 20CONR 33R 82,-(CH 2) oCOOR 75,-(CH 2) oCONR 58R 59,-(CH 2) oPO (OR 60) 2,-(CH 2) pSO 2R 62Or-(CH 2) oCOR 64
R 77Be-C 6R 67R 68R 69R 70R 76Or the heteroaryl of one of following formula
Figure A20058004914100891
R 78Be H, low alkyl group, aryl or aryl lower alkyl;
R 78And R 82Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 79Be H, low alkyl group, aryl or aryl lower alkyl, perhaps
R 78And R 79Can be together :-(CH 2) 2-7-,-(CH 2) 2O (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 80Be H or low alkyl group;
R 81Be H, low alkyl group or aryl lower alkyl;
R 82Be H, low alkyl group, aryl, heteroaryl or aryl lower alkyl;
R 33And R 82Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 83Be H, low alkyl group, aryl or-NR 78R 79
R 84Be-(CH 2) m(CHR 61) sOH ,-(CR 86R 87) pOR 80,-(CR 86R 87) pCOOR 80,-(CH 2) m(CHR 61) sSH ,-(CR 86R 87) pSR 80,-(CH 2) pCONR 78R 79,-(CH 2) pNR 80CONR 78R 79,-(CH 2) pC 6H 4CONR 78R 79,-(CH 2) pC 6H 4NR 80CONR 78R 79,-(CR 86R 87) oPO (OR 60) 2,-(CR 86R 87) pSO 2R 60,-(CR 86R 87) pSOR 60,-(CH 2) m(CHR 61) sOPO (OR 60) 2Or-(CH 2) m(CHR 61) sOSO 2R 60
R 85Be low alkyl group or low-grade alkenyl;
R 86Be low alkyl group or the halogen that H, H can be replaced by halogen;
R 87Be low alkyl group or the halogen that H, H can be replaced by halogen;
Condition is: in the chain of described 11 a-amino acid residue Z,
If-n is 11,1 to 11 amino-acid residue is so:
-P1:C type or D type or E type or F type;
-P2:C type or D type or E type or F type;
-P3:C type or F type, perhaps this residue is Gly;
-P4:C type or D type or F type or E type, perhaps this residue is Gly or Pro;
-P5:E type or C type or F type, perhaps this residue is Gly or Pro;
-P6:D type or F type or E type or C type, perhaps this residue is Gly or Pro;
-P7:C type or E type or F type perhaps have formula-A-CO-, and perhaps this residue is Gly or Pro;
-P8:D type or C type or F type perhaps have formula-A-CO, and perhaps this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or E type or F type;
-P10:D type or C type or F type or E type, and
-P11:C type or D type or E type or F type, perhaps
-P2 and P10 can form the group of H type together, and further condition is: if template is DPro LPro, the amino-acid residue of P1 to P11 position be not following these:
-P1：Arg
-P2: the Cys that connects P10 position Cys by disulfide linkage
-P3：Thr
-P4：Lys
-P5：Ser
-P6：Ile
-P7：Pro
-P8：Pro
-P9：Ile
-P10: by the Cys of disulfide linkage connection P10 position Cys, and
-P11：Phe
According to the present invention, these β-hairpin peptidomimetics can be by following method preparation, and described method comprises:
(a) will be by 5,6 or 7 the derivative coupling of the suitable N-protected of amino acid whose warp in suitably functionalized solid support and the end product of wanting, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(b) remove the N-protected group from thus obtained product;
(c) with the derivative coupling of the suitable N-protected of that amino acid whose warp of a position of more close-terminal amino acid residue in thus obtained product and the end product wanted, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(d) remove the N-protected group from thus obtained product;
(e) repeating step (c) and (d) has been introduced the-terminal amino acid residue up to;
(f) with the compound coupling of thus obtained product and following general formula
Figure A20058004914100921
Wherein
Figure A20058004914100931
As hereinbefore defined, and X is the N-protected group, perhaps, if
Figure A20058004914100932
Be above (a1) or (a2) group,
(fa) with the product of acquisition in the step (e) and the derivative coupling of the suitable N-protected of the amino acid whose warp of following general formula, described general formula is:
HOOC-B-H III or HOOC-A-H
IV
Wherein, B and A as hereinbefore defined, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(fb) remove the N-protected group from thus obtained product; And
(fc) with thus obtained product and the derivative coupling that is respectively the suitable N-protected of amino acid whose warp of above-mentioned general formula I V and III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care; And, respectively, if
Figure A20058004914100933
Be group (a3) above,
(fa ') with the derivative coupling of the suitable N-protected of amino acid whose warp of middle product that obtains of step (e) and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(fb ') removes the N-protected group from thus obtained product; And
(fc ') with the derivative coupling of the suitable N-protected of amino acid whose warp of thus obtained product and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(g) remove the N-protected group from step (f) or the product that obtains (fc) or (fc ');
(h) with thus obtained product and the 11st the derivative coupling of the suitable N-protected of amino acid whose warp in the end product of wanting, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(i) remove the N-protected group from thus obtained product;
(j) with in thus obtained product and the end product wanted from the derivative coupling of the 11st farther one the suitable N-protected of that amino acid whose warp, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(k) remove the N-protected group from thus obtained product;
(l) repeating step (j) and (k) is up to having introduced all amino-acid residues;
(m) if necessary, the one or more shielded functional group selectivity that exists in the molecule is gone protection, and the reaction active groups that discharges is thus suitably replaced;
(n) if necessary, between the side chain of the 2nd and 10 s' suitable amino-acid residue, form the interchain key;
(o) thus obtained product and solid support are broken away from;
(p) will be from cracked product cyclisation on the solid support;
(q) remove any blocking group that exists in any member's the functional group of amino-acid residue chain, and, if necessary, remove other any blocking group that may exist in the molecule; And
(r) if necessary, thus obtained product is converted into its pharmacy acceptable salt, perhaps thus obtained pharmacy acceptable salt or unacceptable salt are converted into corresponding formula I free cpds, perhaps are converted into different, pharmacy acceptable salt.
Perhaps, peptide mimics of the present invention can prepare by following step:
(a ') will be through the suitably functionalized solid support and the compound coupling of following general formula
Figure A20058004914100951
Wherein
Figure A20058004914100952
As hereinbefore defined, and X is the N-protected group, perhaps, if
Be group (a1) or (a2) above,
(solid support that a ' a) is suitably functionalized with described warp and the derivative coupling of the suitable N-protected of the amino acid whose warp of following general formula, described general formula is
HOOC-B-H III or HOOC-A-H IV
Wherein, B and A as hereinbefore defined, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(a ' b) remove the N-protected group from thus obtained product; And
(a ' c) with thus obtained product and the derivative coupling that is respectively the suitable N-protected of amino acid whose warp of above-mentioned general formula I V and III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care; And, respectively, if
Figure A20058004914100954
Be group (a3) above,
The derivative coupling of the solid support that (a ' a ') is suitably functionalized with described warp and the suitable N-protected of amino acid whose warp of above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(a ' b ') removes the N-protected group from thus obtained product; And
(a ' c ') with the derivative coupling of the suitable N-protected of amino acid whose warp of thus obtained product and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(b ') from step (a '), (a ' c) or the product that obtains (a ' c ') are removed the N-protected group;
(c ') with thus obtained product and the 11st the derivative coupling of the suitable N-protected of amino acid whose warp in the end product of wanting, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(d ') removes the N-protected group from thus obtained product;
(e ') with in thus obtained product and the end product wanted from the derivative coupling of the 11st farther one the suitable N-protected of that amino acid whose warp, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(f ') removes the N-protected group from thus obtained product;
(g ') repeating step (e ') and (f ') are up to having introduced all amino-acid residues;
(h ') goes protection to the one or more shielded functional group selectivity that exists in the molecule if necessary, and the reaction active groups that discharges is thus suitably replaced;
(i ') forms the interchain key if necessary between the side chain of the 2nd and 10 s' suitable amino-acid residue;
(j ') breaks away from thus obtained product and solid support;
(k ') will be from cracked product cyclisation on the solid support;
(l ') removes any blocking group that exists in any member's the functional group of amino-acid residue chain, and, if necessary, remove other any blocking group that may exist in the molecule; And
(m ') if necessary, thus obtained product is converted into its pharmacy acceptable salt, perhaps thus obtained pharmacy acceptable salt or unacceptable salt are converted into corresponding formula I free cpds, perhaps are converted into different, pharmacy acceptable salt.
Peptide mimics of the present invention can also be the enantiomer of formula I compound.These enantiomers can prepare by the improvement to aforesaid method, wherein use the enantiomer of all chiral raw material.
When using in this manual, term " alkyl " refers to have the straight chain or the branched saturated hydrocarbyl of 24 at the most (preferably at the most 12) carbon atoms alone or in combination.Similarly, term " thiazolinyl " refer to have 24 at the most (preferably at the most 12) carbon atoms, contain at least one or depend on the chain length straight chain or the band branched hydrocarbyl of four olefinic double bonds at the most.Term " rudimentary " refers to have the group and the compound of 6 carbon atoms at the most.Therefore, for example, term " low alkyl group " refers to have the straight chain or the branched saturated hydrocarbyl of 6 carbon atoms, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl etc. at the most.Term " aryl " refers to contain the aromatic carbon ring alkyl of one or two six-ring, phenyl or naphthyl for example, and it can be replaced by three substituting groups at the most, and described substituting group for example is Br, Cl, F, CF 3, NO 2, low alkyl group or low-grade alkenyl.Term " heteroaryl " refers to contain the aromatic heterocyclic group of one or two five-ring and/or six-ring, at least one contains three heteroatoms at the most in the described ring, described heteroatoms is selected from the group that is made of O, S and N, and described ring is substituted or is not substituted; The representative example of the substituted heteroaryl of examples of such optional is hereinbefore about to R 77Definitional part list.
Structural element-A-CO-refers to the amino acid structure unit, and itself and structural element-B-CO-are combined to form template (a1) and (a2).Structural element-B-CO-and another structural element-B-CO-are combined to form template (a3).Template (a3) is more not preferred in formula I.Template (a) to (p) has been formed the structural unit of the terminal and C-end of the N-with positioned at intervals in the following manner, and described mode makes that the distance between these two groups can be between 4.0-5.5A.Peptide chain Z is terminal and C-is terminal links to each other with the N-end with the C-end of template (a) to (p) by corresponding N-, make template and chain formation ring texture, for example shown in the formula I.As herein under the situation of distance between template N-end and the C-end at 4.0-5.5A, template will induce H-key net, this H-key net is essential for form β-hair clip conformation in peptide chain Z.Thus, template and peptide chain formation β-hair clip stand-in.
β-hair clip conformation is relevant with the serine protease inhibition active height of β of the present invention-hair clip stand-in.Template (a) to the conformation character of the stable β-hair clip of (p) not only has keying action for selective inhibitory activity; it also has keying action to building-up process defined above, can significantly strengthen the cyclisation productive rate because mix template in beginning of the protected peptide precursor of linearity or contiguous intermediary place.
Structural unit A1-A69 belongs to such class of amino acid, and wherein, the N-end is the secondary amine that forms the part of ring.In the amino acid of genes encoding, only proline(Pro) falls into such.The configuration of structural unit A1 to A69 is (D), they with (L)-structural unit of configuration-B-CO-combination.Preferably combination about template (a1) is- DA1-CO- LB-CO-extremely DA69-CO- LB-CO-.Therefore, for example, DPro- LPro has constituted the prototype of template (a1).The more preferred but still more unfeasible combination that forms template (a2) in addition :- LA1-CO- DB-CO-to- LA69-CO- DThe B-CO-combination.Therefore, for example, LPro- DPro has constituted the prototype of template (a2).
Will be appreciated that wherein structural unit-the A1-CO-of A with (D)-configuration carries the radicals R on the alpha-position that is in the N-end to-A69-CO- 1R 1Preferably H and low alkyl group, R 1Most preferably be H and methyl.One skilled in the art will know that A1-A69 shows with (D)-configuration, for R 1Be the situation of H and methyl, it is corresponding to (R)-configuration.According to Cahn, Ingold and Prelog rule are summarized R 1The priority of other value, this configuration also can be represented as (S).
Except R 1Outside, structural unit-A1-CO-is called as R to-A69-CO-portability 2To R 17Other substituting group.This other substituting group can be H, if it is not H, its preferably small size to middle-sized aliphatics or aromatic group.R 2To R 17The example of preferred value be:
-R 2: H, low alkyl group, low-grade alkenyl, (CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl), (CH 2) mSR 56(R wherein 56: low alkyl group or low-grade alkenyl), (CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R 57: H or low alkyl group), (CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 3: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group or R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group), (CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 4: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 5: low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group), (CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group), (CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: alkyl, thiazolinyl, aryl and aryl lower alkyl, heteroaryl-low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 6: H, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 7: low alkyl group, low-grade alkenyl ,-(CH 2) qOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) qSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) qNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) qOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group), (CH 2) qNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) qN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) rCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) qCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) rPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl), (CH 2) rSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl), (CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 9: low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 10: low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 11: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 12: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps; R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) rCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) rCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) rPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 13: low alkyl group, low-grade alkenyl ,-(CH 2) qOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) qSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) qNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) qOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) qNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) qN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) rCOO 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) qCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) rPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) rSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 14: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H, low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) ,-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 15: low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group), (CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl), particularly advantageous NR 20CO low alkyl group (R 20=H or low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 16: low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 17: low alkyl group, low-grade alkenyl ,-(CH 2) qOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) qSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) qNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) qOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) qNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) qN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) rCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) qCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) rPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) rSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
In structural unit A1 to A69, following these are preferred: R 2Be A5, A8, A22, A25, the R of H 2Be A38, A42, A47 and the A50 of H.The structural unit of A8 ' type most preferably:
Figure A20058004914101091
Wherein, R 20Be H or low alkyl group; And, R 64Be alkyl, thiazolinyl, [(CH 2) u-X] t-CH 3(wherein X be-O-,-NR 20Or-S-, u is 1-3, and t is 1-6), aryl, aryl lower alkyl or heteroaryl-low alkyl group; R wherein particularly 64It is n-hexyl (A8 '-1), n-heptyl (A8 '-2), 4-(phenyl) phenmethyl (A8 '-3), diphenyl methyl (A8 '-4), 3-amino-propyl group (A8 '-5), 5-amino-amyl group (A8 '-6), methyl (A8 '-7), ethyl (A8 '-8), sec.-propyl (A8 '-9), isobutyl-(A8 '-10), n-propyl (A8 '-11), cyclohexyl (A8 '-12), cyclohexyl methyl (A8 '-13), normal-butyl (A8 '-14), phenyl (A8 '-15), phenmethyl (A8 '-16), (3-indyl) methyl (A8 '-17), 2-(3-indyl) ethyl (A8 '-18), (4-phenyl) phenyl (A8 '-19), n-nonyl (A8 '-20), CH 3-OCH 2CH 2-OCH 2-and CH 3-(OCH 2CH 2) 2-OCH 2-those.
Structural unit A70 belongs to the alpha-amino group acids of open chain alpha-substitution, and structural unit A71 and A72 belong to corresponding beta-amino acids analogue class, and structural unit A73-A104 belongs to the cyclic analogs class of A70.This type of amino acid derivative has demonstrated and can hold onto the inflection fully defined or little peptide (C.M.Venkatachalam, Biopolymers, 1968,6, the 1425-1434 of U type conformation; W.Kabsch, C Sander, Biopolymers 1983,22, and 2577).Ideally, this type of structural unit or template are suitable for the β-hair clip conformation (D.Obrecht in the stabilized peptide ring, M.Altorfer, J.A.Robinson, " Novel Peptide Mimetic Building Blocksand Strategies for Efficient Lead Finding ", Adv.Med Chem.1999, Vol.4,1-68; P.Balaram, " Non-standard amino acids in peptide designand protein engineering ", Curr.Opin.Struct.Biol.1992,2,845-851; M.Crisma, G.Valle, C.Toniolo, S.Prasad, R.B.Rao, P.Balaram, " β-turn conformations in crystal structures of model peptidescontaining α, α-disubstituted amino acids ", Biopolymers 1995,35,1-9; V.J.Hruby, F.Al-Obeidi, W.Kazmierski, Biochem.J.1990,268,249-262).
Show: two kinds of enantiomerism physical efficiencys of structural unit-A70-CO-to A104-CO-of the structural unit-B-CO-of combination L-configuration are stable expeditiously and induce β-hair clip conformation (D.Obrecht, M.Altorfer, J.A.Robinson, " Novel Peptide MimeticBuilding Blocks and Strategies for Efficient Lead Finding " .Adv.MedChem.1999, Vol.4,1-68; D.Obrecht, C.Spiegler, P.Sch  nholzer, K.M ü ller, H.Heimgartner, F.Stierli, Helv.Chim.Acta 1992,75,1666-1696; D.Obrecht, U.Bohdal, J.Daly, C.Lehmann, P.Sch  nholzer, K.M ü ller, Tetrahedron 1995,51,10883-10900; D.Obrecht, C.Lehmann, C.Ruffieux, P.Sch  nholzer, K.M ü ller, Helv.Chim.Acta 1995,78,1567-1587; D.Obrecht, U.Bohdal, C.Broger, D.Bur, C.Lehmann, R.Ruffieux, P.Sch  nholzer, C.Spiegler, Helv.Chim.Acta 1995,78,563-580; D.Obrecht, H.Karajiannis, C.Lehmann, P.Sch  nholzer, C.Spiegler, Helv.Chim.Acta 1995,78,703-714).
Therefore, with regard to purpose of the present invention, template (a1) also can be made up of-A70-CO-to A104-CO-, and wherein, structural unit A70 to A104 has (D)-or (L)-configuration, and its combination has the structural unit-B-CO-of (L)-configuration.
R among the A70 to A104 20Preferably H or low alkyl group, wherein methyl is the most preferred.R among the structural unit A70 to A104 18, R 19And R 21To R 29Preferred value as follows:
-R 18: low alkyl group.
-R 19: low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) pSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl, R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) pCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) pCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) pSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) oC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 21: H, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl), (CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or (CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 22: low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 23: H, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-, R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl), particularly advantageous be NR 20CO low alkyl group (R 20=H or low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
-R 24: low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl), particularly advantageous be NR 20CO low alkyl group (R 20=H or low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group, or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
-R 25: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 26: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2- 6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps, R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-or, R 25And R 26Can form together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group).
-R 27: H, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl, R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 28: low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59:-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 29: low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl), particularly advantageous be NR 20CO low alkyl group (R 20=H or low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
R 23, R 24And R 29Preferably-NR 20-CO-low alkyl group, wherein R 20Be H or low alkyl group.
For template (b) to (p), for example (b1) and (l), the preferred value of a plurality of symbols is as follows:
-R 1: H or low alkyl group;
-R 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H or low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 20: H or low alkyl group.
-R 30: H, methyl.
-R 31: H, low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl), (CH 2) oCONR 58R 59(R wherein 58: low alkyl group, or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) rC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy); Most preferably-CH 2CONR 58R 59(R 58: H or low alkyl group; R 59: low alkyl group or low-grade alkenyl).
-R 32: H, methyl.
-R 33: low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 34R 63(R wherein 34: low alkyl group or low-grade alkenyl; R 63: H or low alkyl group; Perhaps R 34And R 63Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group), (CH 2) mOCONR 75R 82(R wherein 75: low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 75And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 78R 82(R wherein 20: H or low alkyl group; R 78: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 78And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group).
-R 34: H or low alkyl group.
-R 35: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group).
-R 36: low alkyl group, low-grade alkenyl or aryl lower alkyl.
-R 37: H, low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(wherein R20:H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2 (R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 38: H, low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 78Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 39: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group).
-R 40: low alkyl group, low-grade alkenyl or aryl lower alkyl.
-R 41: H, low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 42: H, low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 43: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60: low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62: low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 44: low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) pSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 78Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) pCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) pCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group or R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) or-(CH 2) oC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 45: H, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) sOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group or R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) or-(CH 2) sC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 46: H, low alkyl group, low-grade alkenyl ,-(CH 2) sOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) sSR 56(R wherein 56: low alkyl group or low-grade alkenyl) ,-(CH 2) sNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) sOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) sNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) sN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group or R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) or-(CH 2) sC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 47: H or OR 55(R wherein 55: low alkyl group or low-grade alkenyl).
-R 48: H or low alkyl group.
-R 49: H; Low alkyl group ,-(CH 2) oCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) or (CH 2) sC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 50: H, methyl.
-R 51: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group), (CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) pCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) pCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) or-(CH 2) rC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 52: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) pCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) pCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) or-(CH 2) rC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 53: H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55: low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33: low alkyl group or low-grade alkenyl; R 34: H or low alkyl group; Perhaps R 33And R 34Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33: H or low alkyl group or low-grade alkenyl; R 75: low alkyl group; Perhaps R 33And R 75Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20: H or low alkyl group; R 33: H or low alkyl group or low-grade alkenyl; R 82: H or low alkyl group; Perhaps R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20: H or low alkyl group; R 64: low alkyl group or low-grade alkenyl) ,-(CH 2) pCOOR 57(R wherein 57: low alkyl group or low-grade alkenyl) ,-(CH 2) pCONR 58R 59(R wherein 58: low alkyl group or low-grade alkenyl; And R 59: H, low alkyl group; Perhaps R 58And R 59Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57: H or low alkyl group) or-(CH 2) rC 6H 4R 8(R wherein 8: H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R 54: low alkyl group, low-grade alkenyl or aryl lower alkyl.
Most preferably, R 1Be H; R 20Be H; R 30Be H; R 31Be carboxymethyl or lower alkoxycarbonyl methyl; R 32Be H; R 35It is methyl; R 36It is methoxyl group; R 37Be H and R 38Be H.
In structural unit A70 to A104, following is preferred: R 22Be A74, A75, A76, the R of H 22Be A77, A78 and the A79 of H.
Template (a1), (a2) and (a3) in structural unit-B-CO-refer to the L-amino-acid residue.Preferred value is-NR concerning B 20CH (R 71)-and R 2Be A5, A8, A22, A25, the R of H 2Be the enantiomer of A38, A42, A47 and the A50 group of H, most preferably:
Ala L-L-Ala
Arg L-arginine
The Asn altheine
Cys L-halfcystine
The Gln L-glutaminate
The Gly glycine
His L-Histidine
Ile L-Isoleucine
Leu L-leucine
Lys L-Methionin
Met L-methionine(Met)
Phe L-phenylalanine
Pro L-proline(Pro)
Pro (5RPhe) (2S, 5R)-5-Phenylpyrrolidine-2-carbocyclic ring acid
Ser L-Serine
Thr L-Threonine
Trp L-tryptophane
Tyr L-tyrosine
Val L-Xie Ansuan
Cit L-citrulline
Orn L-ornithine
TBuA L-tertiary butyl L-Ala
The Sar sarkosine
T-BuG L-tertiary butyl glycine
4AmPhe L-p-Aminophenylalanine
3AmPhe L-m-aminophenyl L-Ala
The adjacent amino-benzene L-Ala of 2AmPhe L-
Phe (mC (NH 2Amidinophenylalaninederivatives between the L-of)=NH)
Phe (pC (NH 2The L-of)=NH) is to Amidinophenylalaninederivatives
Phe (mNHC (NH 2Guanidine radicals phenylalanine between the L-of)=NH)
Phe (pNHC (NH 2The L-of)=NH) is to the guanidine radicals phenylalanine
Phg L-phenylglycocoll
Cha L-Cyclohexylalanine
C 4Al L-3-cyclobutyl L-Ala
C 5Al L-3-cyclopentyl L-Ala
Nle L-nor-leucine
2-Nal L-2-naphthyl L-Ala
1-Nal L-1-naphthyl L-Ala
4Cl-Phe L-4-chlorophenylalanine
3Cl-Phe L-3-chlorophenylalanine
2Cl-Phe L-2-chlorophenylalanine
3,4Cl 2-Phe L-3,4-dichlorobenzene L-Ala
4F-Phe L-4-fluorophenylalanine
3F-Phe L-3-fluorophenylalanine
2F-Phe L-2-fluorophenylalanine
Tic L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
Thi L-β-2-thienyl alanine
Tza L-2-thiazolyl L-Ala
Mso L-methionine sulfoxide
AcLys L-N-ethanoyl Methionin
Dpr L-2, the 3-diaminopropionic acid
A 2Bu L-2, the 4-DAB
Dbu (S)-2, the 3-DAB
Abu γ-An Jidingsuan (GABA)
The Aha epsilon-amino caproic acid
The Aib α-An Jiyidingsuan
Y (Bzl) L-O-phenmethyl tyrosine
Bip L-biphenyl alanine
S (Bzl) L-O-phenmethyl Serine
T (Bzl) L-O-phenmethyl Threonine
HCha L-height-Cyclohexylalanine
HCys L-height-halfcystine
HSer L-height-Serine
HArg L-height-arginine
HPhe L-height-phenylalanine
Bpa L-4-benzoyl phenylalanine
Pip L-pipecolic acid
OctG L-octyl group glycine
MePhe L-N-methylbenzene L-Ala
MeNle L-N-methyl nor-leucine
MeAla L-N-methylalanine
MeIle L-N-methyl Isoleucine
MeVal L-N-methylvaline
MeLeu L-N-methylleucine
In addition, the most preferred value of B also comprises the A8 of (L)-configuration " group of type:
Figure A20058004914101311
R wherein 20Be H or low alkyl group; R 64Be alkyl, thiazolinyl ,-[(CH 2) u-X] t-CH 3(wherein X be-O-,-NR 20-or-S-, u is that 1-3 and t are 1-6), aryl, aryl lower alkyl or heteroaryl-low alkyl group; Especially wherein R 64Be n-hexyl (A8 " 21); n-heptyl (A8 " 22), 4-(phenyl) phenmethyl (A8 " 23); diphenyl methyl (A8 " 24), 3-amino-propyl group (A8 " 25); 5-amino-amyl group (A8 " 26), methyl (A8 " 27); ethyl (A8 " 28), sec.-propyl (A8 " 29); isobutyl-(A8 " 30), n-propyl (A8 " 31); cyclohexyl (A8 " 32), cyclohexyl methyl (A8 " 33); normal-butyl (A8 " 34), phenyl (A8 " 35); phenmethyl (A8 " 36), (3-indyl) methyl (A8 " 37); 2-(3-indyl) ethyl (A8 " 38), (4-phenyl) phenyl (A8 " 39); n-nonyl (A8 " 40), CH 3-OCH 2CH 2-OCH 2-(A8 " 41) and CH 3-(OCH 2CH 2) 2-OCH 2Those of-(A8 " 42).
Usually, define the peptide chain Z of β as herein described-hair clip stand-in with the amino-acid residue that belongs to one of following radicals:
-group C-NR 20CH (R 72) CO-; " hydrophobic: small size is to middle-sized "
-group D-NR 20CH (R 73) CO-; " hydrophobic: big aromatic series or heteroaromatic "
-group E-NR 20CH (R 74) CO-; " polarity is cationic " and " urea deutero-"
-group F-NR 20CH (R 84) CO-; " polarity is uncharged or anionic "
-group H-NR 20-CH (CO-)-(CH 2) 4-7-CH (CO-)-NR 20-,-NR 20-CH (CO-)-(CH 2) pSS (CH 2) p-CH (CO-)-NR 20-,-NR 20-CH (CO-)-((CH 2) pNR 20CO (CH 2) p-CH (CO-)-NR 20-and-NR 20-CH (CO-)-((CH 2) pNR 20CONR 20(CH 2) p-CH (CO-)-NR 20-;
" interchain key "
In addition, the amino-acid residue among the chain Z can also have formula-A-CO-or formula-B-CO-, and wherein, A and B are as hereinbefore defined.At last, Gly also can be the amino-acid residue among the chain Z, and Pro and Pro (4-NHCOPhe) they also can be the amino-acid residues among the chain Z, but except having the position of interchain key (H).
Group C comprise have small size to middle-sized hydrophobic side chain group (according to for substituent R 72General definition) amino-acid residue.Hydrophobic residue refers under physiological pH neutral and the amino acid side chain that is repelled by aqueous solution.In addition, these side chains are hydrogen bonds donor groups not usually, for example (but being not limited to) firsts and seconds acid amides, firsts and seconds amine and its protonated salt, mercaptan, alcohol, phosphonate/ester, phosphate/ester, urea or thiocarbamide accordingly.But they can contain hydrogen bond receptor group, for example ether, thioether, ester, teritary amide, alkyl or aryl phosphonic acid ester and phosphoric acid ester or tertiary amine.The small size of genes encoding to middle-sized amino acid comprises L-Ala, Isoleucine, leucine, methionine(Met) and Xie Ansuan.
Group D comprises and has aromatic series and heteroaromatic side-chain radical (according to for substituent R 73General definition) amino-acid residue.The die aromatischen Aminosaeuren residue refers to have the hydrophobic amino acid of following side chain, and described side chain contains at least one ring, and this ring has conjugated π-electronic system (aromatic group).In addition, they can contain hydrogen bond donor group (such as but not limited to primary amide and secondary amide, primary amine and secondary amine and its corresponding protonated salt, mercaptan, alcohol, phosphonate/ester, phosphate/ester, urea or thiocarbamide) and hydrogen bond receptor group (such as but not limited to ether, thioether, ester, teritary amide, alkyl or aryl phosphonic acid ester and phosphoric acid ester or tertiary amine).The die aromatischen Aminosaeuren of genes encoding comprises phenylalanine and tyrosine.
The heteroaromatic amino-acid residue refers to have the hydrophobic amino acid residue of following side chain, and described side chain has at least one ring, and this ring has conjugated π-electronic system, comprising at least one heteroatoms, such as but not limited to O, S and N (according to for substituent R 77General definition).In addition, this type of residue can contain hydrogen bond donor group (such as but not limited to primary amide and secondary amide, primary amine and secondary amine and its corresponding protonated salt, mercaptan, alcohol, phosphonate/ester, phosphate/ester, urea or thiocarbamide) and hydrogen bond receptor group (such as but not limited to ether, thioether, ester, teritary amide, alkyl or aryl phosphonic acid ester and phosphoric acid ester or tertiary amine).The heteroaromatic amino acid of genes encoding comprises tryptophane and Histidine.
Group E comprises the amino acid that contains following side chain, and described side chain has polarity positively charged ion, amido and urea deutero-residue (according to for substituent R 74General definition).The polarity positively charged ion refers under physiological pH by protonated basic side chain.The polarity cationic amino acid of genes encoding comprises arginine, Methionin and Histidine.Citrulline is the example of urea deutero-amino-acid residue.
Group F comprises the amino acid that contains following side chain, and described side chain has polarity and do not have electric charge or negatively charged ion residue (according to for substituent R 84General definition).Polarity does not have electric charge or the negatively charged ion residue refers to hydrophilic side-chains, its neutral and be negatively charged ion (carboxylic acid is included) respectively under physiological pH, but it can not repelled by aqueous solution.Typically, this type of side chain contains the hydrogen bond donor group, such as but not limited to primary amide and secondary amide, carboxylic acid and ester, primary amine and secondary amine, mercaptan, alcohol, phosphonate/ester, phosphate/ester, urea or thiocarbamide.These groups can form the hydrogen bond net with water molecules.In addition, they also can contain hydrogen bond receptor group, such as but not limited to ether, thioether, ester, teritary amide, carboxylic acid and carboxylicesters (salt), alkyl or aryl phosphonic acid ester and phosphoric acid ester or tertiary amine.The polarity of genes encoding does not have electric charge amino acid and comprises l-asparagine, halfcystine, glutamine, Serine and Threonine, also comprises aspartic acid and L-glutamic acid.
Group H is included in preferably (L)-amino acid whose side chain of beta chain zone relative position, and it can form the interchain key.The key that is widely known by the people most is the disulfide linkage that is formed by the halfcystine that is positioned at the beta chain relative position and height-halfcystine.Known have several different methods to form disulfide linkage, comprises people Synthesis 1979 such as J.P.Tam, 955-957; People such as Stewart, Solid Phase PeptideSynthesis, 2d Ed., Pierce Chemical Company, III., 1984; People J.Biol.Chem.1975 such as Ahmed, 250,8477-8482; With people such as Pennington, Peptides, the 164-166 page or leaf, Giralt and Andreu, Eds., ESCOM Leiden, Holland, 1990 described those.The most advantageously, for scope of the present invention,, can use acetylamino methyl (Acm)-blocking group to prepare disulfide linkage to halfcystine.Fully the interchain key of setting up is the formation by amido linkage, and ornithine is coupled together with the L-glutamic acid and the asparagicacid residue that are positioned at relative beta chain position respectively with Methionin.For the side chain of ornithine and Methionin was amino, preferred blocking group was allyloxycarbonyl (Alloc), is allyl ester for aspartic acid and L-glutamic acid.At last, also can will be positioned at the Methionin of relative beta chain position and the amino of ornithine to couple together, set up the interchain key to form the ring-type urea by using reagent such as N, N-carbonylic imidazole.
As mentioned before, the position that is used for the interchain key is the P2 that lumps together and 10.The known energy of this type of interchain key is stablized β-hair clip conformation, and therefore is configured for designing the important structure element of β-hair clip stand-in.
Among the chain Z most preferred amino-acid residue be from natural a-amino acid deutero-those.Hereinafter listed the amino acid (perhaps their residue) that is suitable for purpose of the present invention, the common way of abridging and adopting corresponding to usually:
Trigram code single-letter code
Ala L-L-Ala A
Arg L-arginine R
Asn altheine N
Asp L-aspartic acid D
Cys L-halfcystine C
Glu L-L-glutamic acid E
Gln L-glutaminate O
Gly glycine G
His L-Histidine H
Ile L-Isoleucine I
Leu L-leucine L
Lys L-Methionin K
Met L-methionine(Met) M
Phe L-phenylalanine F
Pro L-proline(Pro) P
DPro D-proline(Pro) DP
Ser L-Serine S
Thr L-Threonine T
Trp L-tryptophane W
Tyr L-tyrosine Y
Val L-Xie Ansuan V
Other a-amino acid (or its residue) that is suitable for purpose of the present invention comprising:
Cit L-citrulline
Orn L-ornithine
TBuA L-tertiary butyl L-Ala
The Sar sarkosine
Pen L-Trolovol
T-BuG L-tertiary butyl glycine
4AmPhe L-p-Aminophenylalanine
3AmPhe L-m-aminophenyl L-Ala
The adjacent amino-benzene L-Ala of 2AmPhe L-
Phe (mC (NH 2Amidinophenylalaninederivatives between the L-of)=NH)
Phe (pC (NH 2The L-of)=NH) is to Amidinophenylalaninederivatives
Phe (mNHC (NH 2Guanidine radicals phenylalanine between the L-of)=NH)
Phe (pNHC (NH 2The L-of)=NH) is to the guanidine radicals phenylalanine
Phg L-phenylglycocoll
Cha L-Cyclohexylalanine
C 4Al L-3-cyclobutyl L-Ala
C 5Al L-3-cyclopentyl L-Ala
Nle L-nor-leucine
2-Nal L-2-naphthyl L-Ala
1-Nal L-1-naphthyl L-Ala
4Cl-Phe L-4-chlorophenylalanine
3Cl-Phe L-3-chlorophenylalanine
2Cl-Phe L-2-chlorophenylalanine
3,4Cl 2-Phe L-3,4-dichlorobenzene L-Ala
4F-Phe L-4-fluorophenylalanine
3F-Phe L-3-fluorophenylalanine
2F-Phe L-2-fluorophenylalanine
Tic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
Thi L-β-2-thienyl alanine
Tza L-2-thiazolyl L-Ala
Mso L-methionine sulfoxide
AcLys N-ethanoyl Methionin
Dpr 2, the 3-diaminopropionic acid
A 2The Bu 2,4-diamino-butanoic
Dbu (S)-2, the 3-DAB
Abu γ-An Jidingsuan (GABA)
The Aha epsilon-amino caproic acid
The Aib α-An Jiyidingsuan
Y (Bzl) L-O-phenmethyl tyrosine
Bip L-(4-phenyl) phenylalanine
S (Bzl) L-O-phenmethyl Serine
T (Bzl) L-O-phenmethyl Threonine
HCha L-height-Cyclohexylalanine
HCys L-height-halfcystine
HSer L-height-Serine
HArg L-height-arginine
HPhe L-height-phenylalanine
Bpa L-4-benzoyl phenylalanine
4-AmPyrr1 (2S, 4S)-4-amino-tetramethyleneimine-L-carboxylic acid
4-AmPyrr2 (2S, 4R)-4-amino-tetramethyleneimine-L-carboxylic acid
4-PhePyrr1 (2S, 5R)-4-phenyl-tetramethyleneimine-L-carboxylic acid
4-PhePyrr2 (2S, 5S)-4-phenyl-tetramethyleneimine-L-carboxylic acid
5-PhePyrr1 (2S, 5R)-5-phenyl-tetramethyleneimine-L-carboxylic acid
5-PhePyrr2 (2S, 5S)-5-phenyl-tetramethyleneimine-L-carboxylic acid
Pro (4-OH) 1 (4S)-L-oxyproline
Pro (4-OH) 2 (4R)-L-oxyprolines
Pip L-pipecolic acid
DPip D-pipecolic acid
OctG L-octyl group glycine
The NGly sarcosine
MePhe L-N-methylbenzene L-Ala
MeNle L-N-methyl nor-leucine
MeAla L-N-methylalanine
MeIle L-N-methyl Isoleucine
MeVal L-N-methylvaline
MeLeu L-N-methylleucine
DimK L-(N`, N` dimethyl)-Methionin
Lpzp L-piperazine acid (Piperazinic acid)
The acid of Dpzp D-piperazine
Isorn L-(N`, N`-diisobutyl)-ornithine
PipAla L-2-(4`-piperidyl)-L-Ala
PirrAla L-2-(3`-pyrrolidyl)-L-Ala
Ampc 4-amino-piperadine-4-carboxylic acid
NMeR L-N-methylarginine
NMeK L-N-methyllysine
NMePhe L-N-methylbenzene L-Ala
IPegK L-2-amino-6-{2-[2-(2-methoxyl group-oxyethyl group)
Oxyethyl group] kharophen }-caproic acid
SPegK L-2-amino-6-[2-(2 methoxyl groups-oxyethyl group)-second
Amido]-caproic acid
Dab L-2,4-diamino-butyric acid
IPegDab L-2-amino-4{2-[2-(2-methoxyl group-oxyethyl group)-
Oxyethyl group]-kharophen }-butyric acid
SPegDab L-2-amino-4[2-(2 methoxyl groups-oxyethyl group)-second
Amido]-butyric acid
4-PyrAla L-2-(4` pyridyl)-L-Ala
OrnPyr L-2-amino-5-[(2` carbonyl pyrazine)] amino-valeric acid
BnG N-phenmethyl glycine
AlloT not-Threonine
Pro (4NHCOPhe) (2S)-4-benzamidine group-tetramethyleneimine-2-carboxylic acid
Aoc 2-(S)-aminocaprylic acid
For the particularly preferred residue of group C be:
Ala L-L-Ala
Ile L-Isoleucine
Leu L-leucine
Met L-methionine(Met)
Val L-Xie Ansuan
TBuA L-tertiary butyl L-Ala
T-BuG L-tertiary butyl glycine
Cha L-Cyclohexylalanine
C 4Al L-3-cyclobutyl L-Ala
C 5Al L-3-cyclopentyl L-Ala
Nle L-nor-leucine
HCha L-height-Cyclohexylalanine
OctG L-octyl group glycine
MePhe L-N-methylbenzene L-Ala
MeNle L-N-methyl nor-leucine
MeAla L-N-methylalanine
MeIle L-N-methyl Isoleucine
MeVal L-N-methylvaline
MeLeu L-N-methylleucine
Aoc 2-(S)-aminocaprylic acid
For the particularly preferred residue of group D be:
His L-Histidine
Phe L-phenylalanine
Trp L-tryptophane
Tyr L-tyrosine
Phg L-phenylglycocoll
2-Nal L-2-naphthyl L-Ala
1-Nal L-1-naphthyl L-Ala
4Cl-Phe L-4-chlorophenylalanine
3Cl-Phe L-3-chlorophenylalanine
2Cl-Phe L-2-chlorophenylalanine
3,4Cl 2-Phe L-3,4-dichlorobenzene L-Ala
4F-Phe L-4-fluorophenylalanine
3F-Phe L-3-fluorophenylalanine
2F-Phe L-2-fluorophenylalanine
Thi L-β-2-thienyl alanine
Tza L-2-thiazolyl L-Ala
Y (Bzl) L-O-phenmethyl tyrosine
Bip L-biphenyl alanine
S (Bzl) L-O-phenmethyl Serine
T (Bzl) L-O-phenmethyl Threonine
HPhe L-height-phenylalanine
Bpa L-4-benzoyl phenylalanine
PirrAla L-2-(3`-pyrrolidyl)-L-Ala
NMePhe L-N-methylbenzene L-Ala
4-PyrAla L-2-(4` pyridyl)-L-Ala
For the particularly preferred residue of group E be:
Arg L-arginine
Lys L-Methionin
Orn L-ornithine
Dpr L-2, the 3-diaminopropionic acid
A 2Bu L-2, the 4-DAB
Dbu (S)-2, the 3-DAB
Phe (pNH 2) the L-p-Aminophenylalanine
Phe (mNH 2) L-m-aminophenyl L-Ala
Phe (oNH 2) the adjacent amino-benzene L-Ala of L-
HArg L-height-arginine
Phe (mC (NH 2Amidinophenylalaninederivatives between the L-of)=NH)
Phe (pC (NH 2The L-of)=NH) is to Amidinophenylalaninederivatives
Phe (mNHC (NH 2Guanidine radicals phenylalanine between the L-of)=NH)
Phe (pNHC (NH 2The L-of)=NH) is to the guanidine radicals phenylalanine
DimK L-(N`, N` dimethyl)-Methionin
Isorn L-(N`, N`-diisobutyl)-ornithine
NMeR L-N-methylarginine
NMeK L-N-methyllysine
IPegK L-2-amino-6-{2-[2-(2-methoxyl group-oxyethyl group)
Oxyethyl group] kharophen }-caproic acid
SPegK L-2-amino-6-[2-(2 methoxyl groups-oxyethyl group)-second
Amido]-caproic acid
Dab L-2,4-diamino-butyric acid
IPegDab L-2-amino-4{2-[2-(2-methoxyl group-oxyethyl group)-
Oxyethyl group]-kharophen }-butyric acid
SPegDab L-2-amino-4[2-(2-methoxyl group-oxyethyl group)-second
Amido]-butyric acid
OrnPyr L-2-amino-5-[(2` carbonyl pyrazine)] amino-valeric acid
PipAla L-2-(4`-piperidyl)-L-Ala
For the particularly preferred residue of group F be:
The Asn altheine
Asp L-aspartic acid
Cys L-halfcystine
The Gln L-glutaminate
Glu L-L-glutamic acid
Ser L-Serine
Thr L-Threonine
AlloThr not-Threonine
Cit L-citrulline
Pen L-Trolovol
AcLys L-N ε-ethanoyl Methionin
HCys L-height-halfcystine
HSer L-height-Serine
Usually, the peptide chain Z in β of the present invention-hair clip stand-in comprises 11 amino-acid residues.P1 to the P11 position of each amino-acid residue is defined as follows clearly among the chain Z: P1 represents first amino acid among the chain Z, its C-end terminal with its N-and template (b)-(p), or in the template (a1)-the C-end of B-CO-group, template (a2) in-the C-end of A-CO-group, form template (a3) the C-end-the terminal coupling of C-of B-CO-group; P11 represents last amino acid among the chain Z, its N-end terminal with its C-and template (b)-(p), or in the template (a1)-the N-end of A-CO-group, template (a2) in-the N-end of B-CO-group, form template (a3) the N-end-the terminal coupling of N-of B-CO-group.In P1 to the P11 position each preferably contains the amino-acid residue that belongs to one of above-mentioned C, D, E, F, H type, or has formula-A-CO-or have formula-B-CO-, perhaps, is Gly, Pro or Pro (4NHCOPhe), and be as described below:
Generally speaking, 1 of chain Z to 11 a-amino acid residue is preferably:
-P1:C type or D type or E type or F type;
-P2:E type or F type or C type;
-P3:C type or F type, perhaps this residue is Gly;
-P4:C type or E type or F type, perhaps this residue is Gly or Pro;
-P5:E type or F type, perhaps this residue is Gly or Pro;
-P6:C type or D type or F type, perhaps this residue is Gly or Pro;
-P7:F type or formula-A-CO-, perhaps this residue is Gly or Pro;
-P8:D type or C type or formula-A-CO-, perhaps this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or E type or F type;
-P10:F type or C type or E type:
-P11:E type or F type or C type or D type; Perhaps
-P2 and P10 form the group of H type together;
Condition is: if template is DPro- LPro, the amino-acid residue of P1 to P11 position is not so:
-P1：Arg
-P2: the Cys that links to each other with the Cys of P10 position by disulfide linkage
-P3：Thr
-P4 Lys
-P5 Ser
-P6 Ile
-P7 Pro
-P8 Pro
-P9 Ile
The Cys that-P10 links to each other with the Cys of P10 position by disulfide linkage; And
-P11?Phe。
1 to 11 a-amino acid residue most preferably is:
-P1:Nle, Ile, Aoc, hLeu, Chg, OctG, hPhe, 4AmPhe, Cha, Phe, Tyr, 2Cl-Phe, Trp, 1-Nal, Leu, Cha or Arg;
-P2:Cys, Glu, Nle, Thr or Gln;
-P3:Thr, Ala or Abu;
-P4:Lys, Nle, Ala, Abu or Thr;
-P5:Ser, AlloThr or Dpr;
-P6:Ile, c5al, Leu, Nle, Aoc, OctG, Cha, hLeu, hPhe, Chg, t-BuA, Glu or Asp;
-P7：Pro；
-P8:Pro, Ala or Pro (4NHCOPhe);
-P9:Tyr, Phe, Ile, Nle, Cha, Gln, Arg, Lys, His, Thr or Ala;
-P10:Cys, Arg, Nle, Gln, Lys, Met, Thr or Ser;
-P11:Tyr, Gln, Arg, Ser, Nle, 2-Nal, 2Cl-Phe, Cha, Phg, Tyr, Phe, Asp, Asn or Thr; And
-Cys, if exist at P2 and P10, it can form disulfide linkage.
With regard to the inhibitor of cathepsin G, 1 to 11 the a-amino acid residue of chain Z preferably:
-P1:C type or D type or E type;
-P2:F type or C type;
-P3:F type;
-P4:C type or E type;
-P5:E type or F type;
-P6:F type;
-P7:F type or formula-A-CO-, perhaps this residue is Gly or Pro;
-P8:C type or formula-A-CO-, perhaps this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or F type;
-P10:F type or C type or E type;
-P11:E type or D type or F type; Perhaps
-P2 and P10 form the group of H type together.
With regard to the inhibitor of cathepsin G, 1 to 11 a-amino acid residue most preferably is:
-P1:Phe, hPhe, 4AmPhe, Nle, Chg, Ile, Tyr, Arg, Trp, 2Cl-Phe, Arg, 1-Nal or Cha;
-P2:Cys, Glu or Nle;
-P3：Thr；
-P4:Lys or Nle;
-P5:Ser, AlloThr or Dpr;
-P6:Asp or Glu;
-P7：Pro；
-P8：Pro；
-P9:Ile, Nle, Cha, Gln, Tyr or Ala;
-P10:Cys, Arg or Nle;
-P11:Thr, Asp, Ser, Tyr, Phe, Asn or Arg; And
-Cys, if exist at P2 and P10, it can form disulfide linkage.
With regard to the inhibitor of elastoser, 1 to 11 the a-amino acid residue of chain Z preferably:
-P1:C type or D type;
-P2:F type;
-P3:F type or C type;
-P4:C type or F type;
-P5:F type;
-P6:C type;
-P7: formula-A-CO-, perhaps this residue is Gly or Pro;
-P8: formula-A-CO-, perhaps this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:D type or F type or C type;
-P10:F type or C type or E type;
-P11:E type or F type or D type; Perhaps
-P2 and P10 form the group of H type together.
With regard to the inhibitor of elastoser, 1 to 11 a-amino acid residue most preferably is:
-P1:Ile, Nle, Aoc, hLeu, Chg, OctG or hPhe;
-P2:Cys, Glu, Thr or Gln;
-P3:Thr, Ala or Abu;
-P4:Ala, Thr or Abu;
-P5：Ser；
-P6:OctG, Ile, Cha, Leu, c5al, Nle, Aoc, Chg, tBuA or hLeu;
-P7：Pro；
-P8:Pro or Pro (4NHCOPhe);
-P9:Gln, Tyr, ILe or Phe;
-P10:Cys, Lys, Gln, Thr, Met or Arg;
-P11:Tyr, Ser, Arg, Gln, Nle, 2-Nal, 2Cl-Phe, Phe, Cha or Phg; And
-Cys, if exist at P2 and P10, it can form disulfide linkage.
With regard to the inhibitor of tryptase, 1 to 11 the a-amino acid residue of chain Z preferably:
-P1:C type or D type or E type;
-P2:F type;
-P3:F type;
-P4:E type;
-P5:F type;
-P6:C type or D type;
-P7:F type or formula-A-CO-, perhaps this residue is Gly or Pro;
-P8:C type or formula-A-CO-, perhaps this residue is Gly or Pro;
-P9:C type or E type or F type;
-P10:F type;
-P11:E type or D type; Perhaps
-P2 and P10 form the group of H type together;
Condition is: if template is DPro- LPro, the amino-acid residue of P1 to P11 position is not so:
-P1：Arg
-P2: the Cys that links to each other with the Cys of P10 position by disulfide linkage
-P3：Thr
-P4?Lys
-P5?Ser
-P6?Ile
-P7?Pro
-P8?Pro
-P9?Ile
The Cys that-P10 links to each other with the Cys of P10 position by disulfide linkage; And
-P11?Phe。
With regard to the inhibitor of tryptase, 1 to 11 the a-amino acid residue of chain Z most preferably is:
-P1:Cha, Tyr or Trp
-P2：?Cys
-P3：?Thr
-P4：?Lys
-P5：?Ser
-P6：?Leu
-P7：?Pro
-P8：?Pro
-P9：?Lys
-P10：Cys
-P11:Arg; And
The Cys residue that P2 and P10 position exist can form disulfide linkage.
Particularly preferred beta-peptide stand-in of the present invention comprise disclosed as cathepsin G's inhibitor those of embodiment 5,19,20,22,23,38,39,40 and 75; Disclosed as elastase inhibitor those of embodiment 91,121,153,154,155,156,157,158,159,160,161 177 and 178; And disclosed as tryptase inhibitors those of embodiment 193,194 and 195.
Method of the present invention can be used as that parallel array is synthetic advantageously to be implemented, with the library of template fixed β-hairpin peptidomimetics of producing above-mentioned general formula I.This type of parallel synthetic permission obtains the array of a large amount of (common 24 to 192 kinds, preferably, 96 kinds) compound of Formula I with high yield and the purity determined, minimizes the formation of dipolymer and fluorinated polymer.Therefore, the suitable selection through functionalized solid support (being that solid support adds the joint molecule), template and cyclisation site is played an important role.
Can be from the crosslinked polystyrene that preferred 1-5% Vinylstyrene arranged, be coated with the polystyrene (Tentagel of polyoxyethylene glycol spacer (spacer) R) and polyacrylamide resin obtain easily (also to see Obrecht D. through functionalized solid support; Villalgordo, J.-M, " Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries ", Tetrahedron OrganicChemistry Series, Vol.17, Pergamon, Elsevier Science, 1998).
Can be that difunctional spacer molecule comes to carry out functionalized to solid support by joint, this difunctional spacer molecule at one end contains anchoring group, on solid support, contain alternative cracked functional group at the other end, be used for subsequently chemical conversion and cracking program.With regard to purpose of the present invention, use two types joint:
1 type joint be designed to come under acidic conditions, to discharge amide group (Rink H, Tetrahedron Lett.1987,28,3783-3790).The joint of this type forms the acid amides of amino acid carboxyl; Example by this type of joint design functionalized resin comprises 4-[(((2, the 4-Dimethoxyphenyl) aminomethyl phenoxy group kharophen Fmoc-aminomethyl))] PS resin, 4-[(((2, the 4-Dimethoxyphenyl) aminomethyl phenoxy group kharophen Fmoc-aminomethyl))]-4-methyldiphenyl methylamine PS resin (Rink acid amides MBHA PS resin) and 4-[(((2, the 4-Dimethoxyphenyl) the Fmoc-aminomethyl) the phenoxy group kharophen) aminomethyl] benzhydryl amine PS-resin (Rink acid amides BHA PS resin).Preferably, from crosslinked the most preferably polystyrene acquisition upholder of 1-5% Vinylstyrene is arranged, and carry out functionalized to it with 4-(((2, the 4-Dimethoxyphenyl) Fmoc-aminomethyl) phenoxy group kharophen) joint.
2 type joints are designed to the final carboxyl that discharges under acidic conditions.Joint of this type and amino acid whose carboxyl form sour unsettled ester, normally sour unsettled phenmethyl, diphenyl-methyl and trityl ester; The example of this type of joint design comprises 2-methoxyl group-4-hydroxy methyl phenyloxy (Sasrin RJoint), 4-(2,4-Dimethoxyphenyl-methylol)-phenoxy group (Rink joint), 4-(4-methylol-3-methoxyl group phenoxy group) butyric acid (HMPB joint), trityl and 2-chlorine trityl.Preferably, from crosslinked the most preferably polystyrene acquisition upholder of 1-5% Vinylstyrene is arranged, and carry out functionalized to it with 2-chlorine trityl joint.
When method of the present invention is synthesized when implementing as parallel array, it can be according to hereinafter described advantageously implementing, but to those skilled in the art, how these programs being changed when thinking synthetic a kind of single above-mentioned formula I compound, will be directly conspicuous.
To equal will be by parallel mode synthetic compound sum (common 24 to 192 of a large amount of reaction vessels, typically, 96) in load 25 to 1000mg, preferably, 100mg's is suitable for the functionalized solid phase upholder, it preferably has the polystyrene of 1 to 3% Vinylstyrene to obtain from crosslinked, or obtains from the Tentagel resin.
The solvent that uses must be able to make resin expand, and includes but not limited to methylene dichloride (DCM), dimethyl formamide (DMF), N-Methyl pyrrolidone (NMP), dioxane, toluene, tetrahydrofuran (THF) (THF), ethanol (EtOH), trifluoroethanol (TFE), Virahol etc.The solvent mixture that contains at least a component polar solvent (for example, 20%TFE/DCM, 35%THF/NMP) for guaranteeing and the high reaction activity and the solvation of the peptide chain of dissolving and resin-bonded are favourable (Fields, G.B., Fields, C.G., J.Am.Chem.Soc.1991,113,4202-4207).
Along with under solutions of weak acidity, discharging the C-terminal carboxylic acid group and do not influence the exploitation of the multiple joint of the acid-unstable group of functional group in the protection side chain, protected peptide fragment synthetic obtained sizable development.2-methoxyl group-4-salicylic alcohol-deutero-joint (Sasrin RJoint; people such as Mergler; Tetrahedron Lett.1988; 29 4005-4008) available diluted trifluoroacetic acid (TFA of 0.5-1% among the DCM) cracking; and it is stable between synthesis phase Fmoc being removed protective condition at peptide, compatible with this protection scheme based on the Additional Protection group of Boc/tBu.Other joint that is suitable for method of the present invention comprises: the unsettled 4-(2 of super acid, 4-Dimethoxyphenyl-methylol)-phenoxy group joint (Rink joint, Rink, H.Tetrahedron Lett.1987,28,3787-3790), wherein, removing peptide needs among the DCM among 10% acetate or the DCM 0.2% trifluoroacetic acid; 4-(4-methylol-3-methoxyl group phenoxy group) butyric acid deutero-joint (HMPB-joint, Fl  rsheimer; Riniker, Peptides1991,1,990 131), it can also be contained the peptide fragment of all sour unstable side chain protected groups by the 1%TFA/DCM cracking with generation; And also have, 2-chlorine trityl chloride joint (people such as Barlos, Tetrahedron Lett.1989,30,3943-3946), it allows to use the mixture process of Glacial acetic acid/trifluoroethanol/DCM (1: 2: 7) peptide to be dissociated in 30 minutes.
The suitable blocking group that is respectively applied for amino acid and their residue is, for example:
-be used for amino (, for example also in lysine side-chain, existing) as existing
Cbz benzene methoxycarbonyl
The Boc tertbutyloxycarbonyl
The Fmoc 9-fluorenylmethyloxycarbonyl
The Alloc allyloxycarbonyl
Teoc trimethyl silyl ethoxycarbonyl
The Tcc trichloro-ethoxycarbonyl
Nps ortho-nitrophenyl alkylsulfonyl;
Trt trityl group or trityl
-be used for carboxyl (, for example also in aspartic acid and L-glutamic acid side chain, existing) as existing, undertaken by being converted into ester with pure component
The tBu tertiary butyl
The Bn phenmethyl
The Me methyl
The Ph phenyl
The Pac phenacyl
Allyl group
Tse trimethyl silyl ethyl
Tce three chloroethyls;
-be used for guanidine radicals (, for example, in the arginine side chain, existing) as existing
Pmc 2,2,5,7,8-pentamethyl-chroman-6-alkylsulfonyl
Ts tosyl group (being p-toluenesulfonyl)
Cbz benzene methoxycarbonyl
Pbf pentamethyl-Dihydrobenzofuranes-5-alkylsulfonyl
-be used for hydroxyl (, for example, in Threonine and Serine side chain, existing) as existing
The tBu tertiary butyl
The Bn phenmethyl
The Trt trityl
-and be used for sulfydryl (, for example in cysteine side chain, existing) as existing
Acm amido methyl
The tBu tertiary butyl
The Bn phenmethyl
The Trt trityl
Mtr 4-methoxyl group trityl.
Preferably, the amino acid derivative of using 9-fluorenylmethyloxycarbonyl (Fmoc)-protection is used to make up the template fixed beta-hairpin loop mimetics of formula I as structural unit.For going protection, that is, downcut the Fmoc group, can use among the DMF 20% piperidines or the 2%DBU/2% piperidines among the DMF.
The amount of reactant (being amino acid derivative) is generally 1 to 20 equivalent, and this is based on the milliequivalent through the every gram load of functionalized solid phase upholder that is weighed into reaction tube at first (meq/g) (the p-poly-phenyl ethenoid resin typically is 0.1 to 2.85meq/g).If necessary, can use extra normal reactant, be reflected in the rational time with driving and finish.Reaction tube Combined test-tube frame parts (holder block) and manifold (manifold) insert reservoir part (reservoir block) again, and device is fixed to together.The flow through air-flow of manifold of initialize, so that controlled environment to be provided, for example nitrogen, argon gas, air etc.Air-flow also can be heated or cooled before the manifold of flowing through.Heating or cooling to reacting hole are carried out by the reacting by heating platform or with coolings such as Virahol/dry ice, with the building-up reactions that causes wanting.Stir by vibration or magnetic agitation (in reaction tube) and realize.Preferred workstation (but being not limited thereto) is Combi-chem workstation and the MultiSyn Tech ' s-Syro synthesizer of Labsource.
Amido linkage forms needs activation α-carboxyl, is used for the acidylate step.As the carbodiimide class by using always, for example dicyclohexylcarbodiimide (DCC, Sheehan ﹠amp; Hess, J.Am.Chem.Soc.1955,77,1067-1068) or DIC (DIC, people Biochem.Biophys.Res.Commun.1976 such as Sarantakis, 73, when 336-342) carrying out this activation, dicyclohexylurea that obtains and di-isopropyl urea are respectively insoluble and soluble in used usually solvent.In a kind of variation of carbodiimide method, comprise I-hydroxybenzotriazole (HOBt, K  nig ﹠amp; Geiger, Chem.Ber 1970,103,788-798) join in the coupling mixture as additive.HOBt prevents dehydration, contains activated amino acid whose racemization, and plays a role as catalyzer, to advance linked reaction slowly.Some phosphorus reagent is on probation as direct coupling reagent, for example benzotriazole-1-base-oxygen base-three-(dimethylamino)-phosphorus hexafluorophosphate (BOP, people such as Castro, Tetrahedron Lett.1975,14,1219-1222; Synthesis, 1976,751-752) or benzotriazole-1-base-oxygen base-three-pyrrolidyl-phosphorus hexafluorophosphate (Py-BOP, Coste etc., Tetrahedron Lett.1990,31,205-208) or 2-(1H-benzotriazole-1-base-) 1,1,3,3-tetramethyl-urea four (tera) fluoroborate (TBTU) or hexafluorophosphate (HBTU, people such as Knorr, Tetrahedron Lett.1989,30,1927-1930); These phosphorus reagent also are suitable for forming the HOBt ester with shielded amino acid derivative original position.Over closer year, also use two phenoxy group phosphoryl azide things (DPPA) or O-(7-azepine-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TATU) or O-(7-azepine-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU)/7-azepine-I-hydroxybenzotriazole (HOAt, people such as Carpino, TetrahedronLett.1994,35,2279-2281) as coupling reagent.
Owing to must will carry out near quantitative linked reaction, therefore the experimental evidence that needs reaction to finish.Can after each coupling step, carry out ninhydrin reaction (people such as Kaiser, Anal.Biochemistry 1970,34,595) rapidly and easily, wherein, indicate the existence of primary amine quantitatively at five equilibrium and the positive colorimetric reaction of peptide resin-bonded.The Fmoc chemical process allow when discharging the Fmoc chromophoric group with alkali to its carry out Spectrophotometric Assays (people such as Meienhofer, Int.J.Peptide Protein Res.1979,13,35-42).
Wash with intermediate product resin-bonded in each reaction tube, make it not contain excessive retention reagent, solvent and by product, washing is undertaken for pure solvent by repeated exposure, and this realizes with one of following two kinds of methods:
1) solvent of packing in reacting hole (preferably, 5ml), immerses reaction tube and test-tube stand parts and manifold, stirred 5 to 300 minutes, preferably, 15 minutes, and, then discharge solvent by the air pressure of using through manifold inlet (closing outlet simultaneously) by the gravity discharge;
2) remove menifold from the test-tube stand parts, (preferably, 5ml) scatter, via strainer it is drained in the receiving vessel (for example test tube or tubule) by gravity by the five equilibrium of reaction tube top with solvent.
Above-mentioned two kinds of washing procedures are repeated to (preferably, about 10 times) much about 50 times, by method such as TLC, GC or observe the efficient that washes comes monitoring reagent, solvent and by product to remove.
Each transform continuously, all repeat mentioned abovely will in reacting hole, react the program of then removing excess reagent, by product and solvent, up to the peptide that has obtained the linearity that last and quilt resin-bonded protect fully with the compound and the reagent of resin-bonded.
Before the peptide of the linearity that this quilt is protected fully dissociates from solid support, if necessary, can carry out selectivity to the one or more shielded functional group that exists in the molecule and go protection, and suitably replace the reaction active groups that discharges thus.For reaching this effect, must be at first want the functional group that handles with the blocking group protection of all the other blocking groups that can be selectively removed and can not have influence on existence.Alloc (allyloxycarbonyl) can be selectively removed (for example to pass through CH 2Cl 2In phenyl silane and Pd °) and can not influence the example of this type of amido protecting group of all the other blocking groups (for example Fmoc) that exist in the molecule.Availablely then be suitable for introducing the reaction active groups that the substituent agent treated wanted discharges thus.Thus, for example, can by corresponding to the acylating reagent of the acyl substituent that will introduce to amino acidylate in addition.For forming the amino acid of pegization, for example IPegK or SPegK, preferably, with 5 normal HATU (phosphofluoric acid N-[(dimethylamino)-1H-1 in the dry DMF, 2,3-triazolo [4,5-b] pyridine-1-methylene]-N-methyl first ammonium N-oxide compound) solution and anhydrous DMF in 10 normal DIPEA (diisopropylethylamine) solution, and respectively, 5 normal 2-[2-(2-methoxy ethoxy) oxyethyl group] acetate (lPeg) and 2-(2-methoxy ethoxy) acetate (sPeg) is applied to amino last 3 hour that discharges of suitable amino acid side chain.After this after resin is filtered and washs, repeat this program 3 hours again with the fresh solution of reagent.
Before the peptide of the linearity that this quilt is protected fully disintegrates down from solid support, if necessary, can also between the suitable amino-acid residue side chain on 2 and 10, form the interchain key.
Above in conjunction with about the explanation that group carried out of H type, interchain key and formation thereof are discussed, the group of H type for example can be the disulfide linkage that forms by between halfcystine on the relative position of beta chain and homocysteine residue, or by amido linkage by being positioned at locational L-glutamic acid and the asparagicacid residue that links to each other with lysine residue with ornithine respectively of relative beta chain, the perhaps lactam bridges that forms by the glutaminic acid residue that links to each other with the 2,4-diamino-butanoic residue.The formation of this type of interchain key can realize by means commonly known in the art.
For forming disulfide linkage, preferably, 10 normal iodine solutions are applied among the DMF, perhaps be applied to CH 2Cl 2In/MeOH the mixture 1.5 hours, after filtering iodine solution, repeat again to carry out 3 hours again with fresh iodine solution, perhaps 10 normal iodine solutions are applied to mixture (the NaHCO of DMSO and acetic acid solution with 5% 3Be buffered to pH 5-6) in 4 hours, perhaps be adjusted in the water of pH 8 by stirring to apply it in 24 hours with solution of ammonium hydroxide, perhaps in the presence of air, be applied in the ammonium acetate buffer that is adjusted to pH 8, perhaps be applied to (preferably, 50 equivalents) in NMP and the tri-n-butyl phosphine.
By reaction tube and test-tube stand parts and manifold are immersed the reacting hole that contains lytic reagent solution (preferably, 3 to 5ml), the peptide of realizing the linearity protected fully dissociating from the solid support.Gas flow, temperature control, stirring and reaction monitoring carry out according to mentioned above and demand, to realize dissociation reaction.Remove reaction tube and pipe support parts and manifold from reservoir part, it is promoted to is higher than the solution water plane but is lower than the reacting hole upper edge, use air pressure (closing outlet simultaneously) via manifold inlet, so that end product solution is efficiently arranged in the storage holes.According to mentioned above, with 3 to 5ml suitable solvents resin remaining in the reaction tube is washed 2 to 5 times, then to extract (washing out) dissociating product as much as possible.Merge thus obtained product solution, carefully carry out, mix to avoid intersecting.Operate various solution/extracts then according to demand, to isolate final compound.Typical operation includes but not limited to: evaporation, concentrate, other reaction in liquid/liquid extraction, acidifying, alkalization, neutralization or the solution.
To contain from solid support downcut and with the alkali and the solution of the linear peptides derivative protected fully of the quilt of mistake evaporate.Use solvent then, for example DCM, DMF, dioxane, THF etc. carry out cyclisation in solution.The multiple coupling reagent that preamble was mentioned all can be used for cyclisation.Cyclisation continues about 6-48 hour, preferably, and about 16 hours.For example follow the tracks of reaction process by RP-HPLC (reversed-phased high performace liquid chromatographic).Remove by evaporation then and desolvate, the cyclic peptide derivative that will be protected fully be dissolved in the immiscible solvent of water (for example DCM) in, and the mixture extraction solution of water or water miscible solvent is to remove any excessive coupling reagent.
At last, with 95%TFA, 2.5%H 2O, 2.5%TIS or be used to realizes that other of scavenging agent of cracking blocking group makes up and handles the peptide derivant of being protected fully.The scission reaction time is generally 30 minutes to 12 hours, preferably, and about 2.5 hours.Volatile matter is evaporated to dried, among the 20%AcOH that rough peptide is dissolved in the water, extracts with isopropyl ether or other solvent of being suitable for this.Collect aqueous layer, be evaporated to driedly, obtain by the cyclic peptide derivative of complete de-protected formula I as end product.
Perhaps, can be in Glass Containers manual realize from solid support dissociate, cyclisation and thoroughly remove to protect the peptide of being protected fully.
According to its purity, this peptide derivant can be directly used in biological test, perhaps must be further purified it, for example comes purifying by preparation property HPLC.
As mentioned before; if necessary; the complete de-protected product of the quilt of thus obtained formula I can be converted into pharmacy acceptable salt afterwards; or thus obtained pharmaceutically acceptable or unacceptable salt is converted into the free cpds of corresponding formula I, perhaps be converted into different, pharmacy acceptable salt.Anyly all can carry out by means commonly known in the art in these operations.
Be used for the template raw material of the formula II of method of the present invention, preceding raw material (pre-starting materials) material that is used for it and the preparation of these raw materials and preceding raw material and described at International Application PCT/EP02/01711 of same applicant, this application is open as WO02/070547 A1.
β-hairpin peptidomimetics of the present invention can be used in the application of wide scope, wherein, inflammatory diseases or pulmonary disorder or infection or Immunological diseases or cardiovascular disorder or neurodegenerative disease are mediated by serine protease or cause, perhaps wherein, cancer is mediated by serine protease or causes.Be the illness that given available proteinase inhibitor is treated or the control or the prevention of disease, can use β-hairpin peptidomimetics itself or it is used as the appropriate formulation with carrier well known in the art, thinner or vehicle.
When β-hairpin peptidomimetics is used for the treatment of or prevents pulmonary emphysema, rheumatoid arthritis, osteoarthritis, arteriosclerosis, psoriasis, cystic fibrosis, multiple sclerosis, adult respiratory distress syndrome, pancreatitis, asthma, allergic rhinitis, the inflammatory skin disease, postangioplasty restenosis, cardiac hypertrophy, heart failure or cancer (such as but not limited to, mammary cancer or with vascularization or shift relevant cancer) etc. during disease, β-hairpin peptidomimetics can be used separately, mixture as multiple β-hairpin peptidomimetics is used, with other anti-inflammatory agents or antimicrobial medicament or anticancer agent combined administration, and/or has the forms of pharmacologically active agents combined administration with other.But β-hairpin peptidomimetics former state is used, or is used as pharmaceutical composition.
Can by traditional mixing, dissolving, granulation, manufacturing coated tablet, fine grinding, emulsification, encapsulated, entrain into the pharmaceutical composition that (entrap) or freeze drying process production comprise β-hairpin peptidomimetics of the present invention.Can use one or more physiology acceptable carriers, thinner, vehicle or assistant agent (it helps active β-hairpin peptidomimetics is processed as pharmaceutically spendable preparation), come the compounding pharmaceutical composition with traditional means.Appropriate formulations depends on selected application process.
For topical application, β-hairpin peptidomimetics of the present invention can be formulated as solution, gelifying agent, ointment, creme, suspension etc., this is well known in the art.
The systematicness preparation comprises and is designed for those that use by injection (in for example subcutaneous, intravenously, intramuscular, the sheath or peritoneal injection), and be designed for transdermal, saturating mucous membrane, per os or use through lung those.
For injection, β-hairpin peptidomimetics of the present invention can be formulated in the suitable solution, preferably, in the physiology compatible buffers, for example, in Hink ' s solution, Ringer's solution or the normal saline buffer solution.Solution can contain prescription material, for example suspension agent, stablizer and/or dispersion agent.Perhaps, β-hairpin peptidomimetics of the present invention can be a powder type, is used for before use and the suitable medium pyrogen-free water of sterilization (for example through) combination.
For saturating mucosal administration, in preparation, use permeate agent suitable for the barrier that will penetrate, this is known in the art.
For dosage forms for oral administration, can be easy to prepare them by with β-hairpin peptidomimetics of the present invention and pharmaceutically acceptable carrier combinations known in the art.Examples of such carriers can make β-hairpin peptidomimetics of the present invention be configured to tablet, pill, drageeing, capsule, liquid, gelifying agent, syrup, slurry, suspension etc., is used for by patient's oral preparations to be treated.For oral preparations (for example powder, capsule and tablet), suitable vehicle comprises filler (sugar for example, for example lactose, sucrose, mannitol and Sorbitol Powder; Preparation of cellulose thing, for example W-Gum, wheat starch, rice fecula, yam starch, gelatin, tragacanth, methylcellulose gum, HPMC, Xylo-Mucine and/or polyvinylpyrrolidone (PVP)), granulation agent and tackiness agent.If necessary, can add disintegrating agent, for example through crosslinked polyvinylpyrrolidone class, agar or alginic acid or its salt (for example sodium alginate).If necessary, can use standard technique to solid dosage sugar coating or bag casing.
For oral liquid (for example suspension, elixir and solution), suitable carriers, vehicle or thinner comprise water, glycol, oil, alcohol etc.In addition, also can add the agent of tender flavor, sanitas, tinting material etc.
For using through cheek, composition can adopt forms such as the tablet, lozenge of common preparation.
For using by suction, use suitable propelling agent, for example Refrigerant 12, trichlorofluoromethane, carbonic acid gas or other suitable gas can be sent the β-hairpin peptidomimetics of the present invention of aerosol spray form easily from pressurized package or atomizer.Under the aerocolloidal situation of pressurization, can determine dose unit by providing valve to send through the amount of metering.Be used for the capsule of for example gelatin of sucker or insufflator and cartridge case and can be configured to the powdered mixture that contains β-hairpin peptidomimetics of the present invention and suitable powder matrix (for example lactose or starch).
Compound also can be configured to rectum or compositions for vaginal use, for example with the suppository of suitable suppository base (for example theobroma oil or other glyceryl ester).
Except that the described preparation of preamble, β-hairpin peptidomimetics of the present invention also can be configured to depot formulation.This type of prolonged action preparation can be by implanting (for example subcutaneous or intramuscular is implanted) or using by intramuscularly.For producing this type of depot formulation, β-hairpin peptidomimetics of the present invention can be prepared with suitable polymers or hydrophobic material (for example as the emulsion in the acceptable oil) or ion exchange resin, perhaps as sl. sol. salt preparation.
In addition, can use the other medicines delivery system, liposome for example well known in the art and emulsion.Can also use some organic solvent, for example methyl-sulphoxide.In addition, can use slow-released system, the semipermeability matrix that for example contains the solid polymer of healing potion is sent β-hairpin peptidomimetics of the present invention.Determined multiple slow-release material, they are well known to a person skilled in the art.Slow releasing capsule can discharge compound and continue several weeks until surpassing 100 days, and this depends on their chemical property.According to the chemical property and the biological stability of healing potion, can use extra strategy to be used for protein stabilization.
Because β-hairpin peptidomimetics of the present invention may contain charged residue, they can be wrapped in any above-mentioned preparation by former state, perhaps include as pharmacy acceptable salt.Than corresponding free form, the solubleness of pharmacy acceptable salt in water-based or other protic solvent trends towards bigger.
The amount of the purpose that β-hairpin peptidomimetics of the present invention or its composition will be wanted with effective realization is usually used.Should be appreciated that used amount will depend on specific application.
For carrying out topical application, the disease of available beta hairpin stand-in treatment is treated or prevent, can use, for example the treatment effective dose is measured in the in vitro tests that provides among the embodiment.Can be in disease visible or even when it is also sightless application of treatment.Those of ordinary skills need not carry out too much experiment, can be identified for treating the treatment significant quantity of local disease.
For the general administration, can estimate the treatment significant quantity from vitro tests at first.For example, can be prepared dosage in animal model, to obtain circulation β-hairpin peptidomimetics concentration range, it comprises the IC that measures in the cell culture 50This type of information can be used for determining more accurately the effective dose in the mankind.
Can use technology well known in the art, data in the body, for example animal model is determined predose.Those of ordinary skills can easily optimize using at the mankind based on animal data.
Can individuation regulate and be used for the dosage used as serpin, so that the blood plasma level of the β-hairpin peptidomimetics of the present invention that is enough to keep result of treatment to be provided.Can obtain by using many doses every day treating effective serum level.
Under the situation of topical application or selectivity absorption, effective partial concn of β-hairpin peptidomimetics of the present invention may be irrelevant with plasma concentration.Those of ordinary skills can optimize the effective local dose of treatment, and need not to carry out too much experiment.
The amount of β-hairpin peptidomimetics of certainly, using will depend on severity, method of application and the prescriber's of the experimenter that treated, experimenter's body weight, sufferer judgement.
Usually, the treatment effective dose of β-hairpin peptidomimetics as herein described will provide the treatment benefit, and can not cause substantial toxicity.
Can in cell culture or laboratory animal, measure the toxicity of β-hairpin peptidomimetics of the present invention by the standard drug program, for example, by measuring LD 50(dosage that causes 50% death in the colony) or LD 100(dosage that causes colony's 100% death) obtains.Dosage ratio between toxicity and the result of treatment is a therapeutic index.The compound that shows high therapeutic index is preferred.The data that obtain from these cell culture tests and zooscopy can be used for preparing nontoxic dosage range concerning being used for the mankind.Preferably in the circulation composition of following ranges, this concentration comprises does not have or does not almost have toxic effective dose to the dosage of β-hairpin peptidomimetics of the present invention.Dosage can change in this scope, and this depends on the dosage form of use and used route of administration.Can consider that status of patient selects preparation, route of administration and dosage accurately by individual doctor.(see, for example, people such as Fingl 1975, at The Pharmacological Basis ofTherapeutics, Ch.1, p.1 in).
Following embodiment sets forth the present invention in more detail, but does not desire by any way scope of the present invention to be limited.Used following abbreviation among these embodiment:
HBTU:1-benzotriazole-1-base-tetramethyl-urea hexafluorophosphate (people Tetrahedron Lett.1989 such as Knorr, 30,1927-1930);
The HOBt:1-hydroxybenzotriazole;
DIEA: diisopropylethylamine;
HOAT:7-azepine-I-hydroxybenzotriazole;
HATU:O-(7-azepine-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (people Tetrahedron Lett.1994 such as Carpino, 35,2279-2281).
Embodiment
1. peptide is synthetic
With first kind of shielded amino-acid residue and resin coupling
With 0.5g 2-chlorine trityl chloride resin (people Tetrahedron Lett.1989 such as Barlos, 30,3943-3946) (0.83mMol/g 0.415mmol) packs in the exsiccant flask.Resin is suspended in CH 2Cl 2(2.5ml), continue to stir 30 minutes, be allowed to condition under the room temperature and expand.With first kind of 0.415mMol (1 equivalent) by amino-acid residue of due care (seeing below) and CH 2Cl 2284 μ l (2.5ml) (4 equivalents) diisopropylethylamine (DIEA) is handled resin, and mixture was 25 ℃ of vibrations 4 hours.Color of resin becomes purple, and it is light yellow that solution keeps.Vibration resin (CH 2Cl 2/ MeOH/DIEA:17/2/1), 30ml continues 30 minutes; Washing in the following sequence then: use CH 2Cl 2(1x), DMF (1x), CH 2Cl 2(1x), MeOH (1x), CH 2Cl 2(1x), MeOH (1x), CH 2Cl 2(2x), Et 2O (2x) washes, and under vacuum dry 6 hours.
Typically, heap(ed) capacity is 0.6-0.7mMol/g.
The resin for preparing following preload: Fmoc-Pro-2-chlorine trityl resin, Fmoc-Asp (OtBu)-2-chlorine trityl resin, Fmoc-Pro (5RPhe)-2-chlorine trityl resin, Fmoc-Leu-2-chlorine trityl resin, Fmoc-Glu (OtBu)-2-chlorine trityl resin, Fmoc-Asp (OtBu)-2-chlorine trityl resin, Fmoc-Phe-2-chlorine trityl resin, Fmoc-Gln (Trt)-2-chlorine trityl resin, Fmoc-Ser (OtBu)-2-chlorine trityl resin, Fmoc-Val-2-chlorine trityl resin, Fmoc-Thr (OtBu)-2-chlorine trityl resin and Fmoc-Ile-2-chlorine trityl resin.
The peptide fragment that synthetic quilt is protected fully
Use 24 to 96 reaction vessels, use Syro-peptide synthesizer (Multisyntech) to synthesize.In each container, place the above-mentioned resin of 60mg (weight resin before loading).Configure following reaction cycle, and it carried out:
Step Reagent Time
1 2 3 4 5 6 7 CH 2Cl 2, the washing and (the manually carrying out) DMF that expands wash and 40% piperidines that expands/DMF DMF, wash 5 normal Fmoc amino acid/DMF+5eq.HBTU+5eq.HOBt+5eq.DIEA DMF and wash CH 2Cl 2, washing (when end of synthesis) 3 * 1 minutes 1 * 5 minute 1 * minute 5 * 2 minutes 1 * 120 minute 4 * 2 minutes 3 * 2 minutes
Repeating step 3 to 6 is to add each amino acid.
After the peptide fragment that has stopped being protected fully synthetic, adopt hereinafter described program A or program B subsequently, this depends on whether will form the interchain key on (i.e. two sulphur beta chain keys).
Program A: main chain is by the cyclisation of the peptide of cyclisation and aftertreatment
The peptide fragment that cracking is protected fully
Finish synthetic after, resin is suspended in CH 2Cl 2In 1ml (0.39mMol) 1%TFA (v/v) in, suspended 3 minutes, filter, use CH 2Cl 2In 1ml (1.17mMol, 3 equivalents) 20%DIEA (v/v) neutralization filtrate.This program repeats twice, to guarantee to finish cracking.With the 0.5ml cleavage mixture five equilibrium sample (200 μ L) filtrate is gone protection fully; described cleavage mixture contains 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% tri isopropyl silane (TIS); by anti-phase-LC MS filtrate is analyzed, with monitoring linear peptides synthetic efficient.
The cyclisation of linear peptides
The linear peptides that to be protected fully is dissolved among the DMF (8ml, concentration is 10mg/ml).4 normal DIEA (1.44mMol) among 2 normal HATU (0.72mMol) and the 1ml DMF at room temperature carry out 16 hours stirring among the adding 1ml DMF to mixture.The evaporation volatile matter is to doing.Rough cyclisation peptide is dissolved in 7ml CH 2Cl 2In, the 10% acetonitrile extraction in the water (4.5ml) three times.With CH 2Cl 2Layer is evaporated to dried.
Cyclic peptide go the protection and purifying
The cyclic peptide that obtains is dissolved in the 3ml cleavage mixture, contains 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% tri isopropyl silane (TIS) in this mixture.Mixture was placed 2.5 hours at 20C, under vacuum, concentrated then.Rough peptide is dissolved among the 20%AcOH in the water (7ml), with diisopropyl ether (4ml) extraction three times.Collect aqueous layer, be evaporated to dried, by the anti-phase LC-MS purifying resistates of preparation property.
After the freeze-drying, obtain the product of white powder form, analyze by LC-MS.The purity that comprises that obtains after preparation property HPLC and the ESI-MS is shown in the table 1 at interior analytical data.
Analytical procedure:
Use Jupiter Proteo 90A, 150 * 2.0mm, (code 00F4396-B0-Phenomenex) come determination and analysis HPLC retention time (RT, in minute), wherein use following solvents: solvent orange 2 A (H 2O+0.1%TFA) and solvent B (CH 3CN+0.1%TFA), and use following gradient: 0 minute: 95%A, 5%B; 20 minutes: 40%A, 60%B; 21-23 minute: 0%A, 100%B; 23.1-30 minute: 95%A, 5%B.
Program B: the main chain with two sulphur beta chain keys is formed two sulphur beta chain keys by the cyclisation of the peptide of cyclisation and aftertreatment
Finish synthetic after, resin was expanded 1 hour in the dry DMF of 3ml.In reactor, add 10 normal iodine solutions among the DMF (6ml) then, then stirred 1.5 hours.Filter resin, add fresh iodine (10 equivalents) solution among the DMF (6ml), then restir is 3 hours.Filter resin, with DMF (3x) and CH 2Cl 2(3x) washing.
Backbone cyclized, the cracking of peptide and purifying
Form after the two sulphur beta chain keys, resin is suspended in CH 2Cl 2In the 1%TFA (v/v) of 1ml (0.39mMol) in, suspended 3 minutes, filter, use CH 2Cl 2In 20%DIEA (v/v) neutralization filtrate of 1ml (1.17mMol, 3 equivalents).This program repeat twice complete to guarantee cracking.Use 2ml CH 2Cl 2Washing resin.Evaporation CH 2Cl 2Layer is to doing.
The linear peptides that to be protected fully is dissolved in the dry DMF of 8ml.In peptide, add in the dry DMF (1ml) 4 normal DIPEA in 2 normal HATU and the dry DMF (1ml) then, then stirred 16 hours.Volatile matter is evaporated to dried.The rough peptide through cyclisation is dissolved in 7ml CH 2Cl 2In, the extraction of 10% acetonitrile is three times in the water (4.5ml).Evaporation CH 2Cl 2Layer is to doing.For peptide being gone fully protection, add 3ml cracking mixed solution TFA: TIS: H 2O (95: 2.5: 2.5), mixture was placed 2.5 hours.Volatile matter is evaporated to dried, and rough peptide is dissolved among the 20%AcOH in the water (7ml), with diisopropyl ether (4ml) extraction three times.Collect water layer, be evaporated to dried, by the anti-phase LC-MS purifying resistates of preparation property.
After the freeze-drying, obtain the product of white powder form, analyze by ESI-MS analytical procedure mentioned above.The purity that comprises that obtains after preparation property HPLC and the ESI-MS is shown in the table 1 at interior analytical data.
Embodiment 1-45,52-63,65-67,70-71,75-114,129,131-162 and 179-196 are shown in the table 1.Begin synthetic peptide from amino acid Pro with the resin grafting.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Embodiment 1-6,9-45,52-63,65-67,70-71,75-103,112-114,129,131,133,136-138,140-141,143-146,148-153,155,157-162 and 179-196 are according to described in the program B; cracking from the resin is carried out disulfide linkage formation, cyclisation, is removed protection and purifying.Embodiment 82,123,149,159,161 and 178 is according to cracking from the resin described in the program B.Use following program to form disulfide linkage:
Rough product is dissolved in (concentration: 1mg raw product among every ml) among the ammonium acetate buffer 0.1M (pH regulator is 8).At room temperature stir the mixture existing under the situation of air.By anti-phase LC-MS monitoring reaction.After reacting completely, evaporating solns is to doing, by the anti-phase LC-MS purifying resistates of preparation property.
According to the cyclisation of carrying out main chain described in the program A.Use following program to go protection:
For peptide being gone fully protection, add 5ml cracking mixed solution TFA: H 2O: phenol: sulfo-phenylmethylether: dithioglycol (82.5: 5: 5: 5: 2.5), mixture was at room temperature placed 5 hours.Come precipitation of peptides by adding cold diethyl ether (10ml).After centrifugal, remove the supernatant liquid phase.It is inferior with the 5ml diethyl ether throw out to be given a baby a bath on the third day after its birth, and anti-phase LC-MS carries out purifying by preparation property.
After the freeze-drying, obtain the product of white powder form, analyze by ESI-MS analytical procedure mentioned above.
Embodiment 7,8,104-111,132,134,135,139,142,147,154 and 156 carry out cyclisation, remove protection and purifying according to cracking from the resin described in the program A.
Use above-mentioned analytical procedure, mensuration HPLC-retention time (minute):
Embodiment 1 (15.37), embodiment 2 (11.54), embodiment 3 (7.82), embodiment 4 (8.62), embodiment 5 (16.51), embodiment 6 (13.67), embodiment 7 (3.61), embodiment 8 (4.11), embodiment 9 (5.82), embodiment 10 (7.98), embodiment 11 (8.38), embodiment 12 (6.80), embodiment 13 (7.41), embodiment 14 (6.20), embodiment 15 (8.68), embodiment 16 (9.82), embodiment 17 (5.59), embodiment 20 (7.32), embodiment 21 (8.66), embodiment 22 (8.68), embodiment 23 (12.66), embodiment 24 (8.67), embodiment 25 (7.53), embodiment 26 (9.02), embodiment 27 (8.06), embodiment 28 (9.62), embodiment 29 (8.78), embodiment 30 (10.49), embodiment 31 (5.50), embodiment 32 (7.45), embodiment 33 (8.39), embodiment 34 (10.16), embodiment 35 (9.04), embodiment 36 (10.98), embodiment 37 (7.56), embodiment 38 (9.29), embodiment 39 (8.32), embodiment 40 (10.11), embodiment 41 (7.23), embodiment 42 (8.83), embodiment 43 (7.92), embodiment 44 (9.87), embodiment 45 (8.26), embodiment 52 (6.20), embodiment 53 (8.68), Ex54 (9.82), embodiment 55 (5.59), embodiment 56 (6.06), embodiment 57 (6.47), embodiment 58 (7.32), embodiment 59 (8.68), embodiment 60 (10.66), embodiment 61 (8.54), embodiment 62 (9.83), embodiment 63 (16.54), embodiment 65 (15.71), embodiment 66 (17.50), embodiment 67 (15.87), embodiment 70 (12.87), embodiment 71 (13.48), embodiment 75 (14.22), embodiment 76 (4.47), embodiment 77 (5.15), embodiment 78 (10.93), embodiment 79 (10.70), embodiment 80 (12.09), embodiment 81 (11.63), embodiment 82 (5.71), embodiment 83 (5.45), embodiment 84 (11.14), embodiment 85 (10.90), embodiment 86 (13.78), embodiment 87 (13.98), embodiment 88 (14.35), embodiment 89 (15.21), embodiment 90 (14.72), embodiment 91 (11.97), embodiment 92 (11.77), embodiment 93 (15.25), embodiment 94 (14.61), embodiment 95 (20.46), embodiment 96 (15.08), embodiment 97 (20.78), embodiment 98 (18.28), embodiment 99 (14.62), embodiment 100 (13.90), embodiment 101 (13.76), embodiment 102 (20.53), embodiment 103 (14.14), embodiment 104 (11.60), embodiment 105 (11.90), embodiment 106 (11.63), embodiment 107 (11.78), embodiment 108 (13.03), embodiment 109 (15.22), embodiment 110 (12.40), embodiment 111 (12.10), embodiment 112 (5.49), embodiment 113 (5.67), embodiment 114 (5.55), embodiment 129 (17.22), embodiment 131 (11.97), embodiment 132 (13.56), embodiment 133 (14.57), embodiment 134 (14.72), embodiment 135 (17.53), embodiment 136 (18.28), embodiment 137 (14.72), embodiment 138 (14.35), embodiment 139 (15.40), embodiment 140 (11.14), embodiment 141 (5.71), embodiment 142 (13.97), embodiment 143 (13.94), embodiment 144 (15.08), embodiment 145 (20.87), embodiment 146 (17.91), embodiment 147 (17.11), embodiment 148 (7.83), embodiment 149 (16.22), embodiment 150 (20.09), embodiment 151 (20.72), embodiment 152 (21.38), embodiment 153 (17.97), embodiment 154 (16.58), embodiment 155 (19.46), embodiment 156 (15.66), embodiment 157 (22.04), embodiment 158 (15.65), embodiment 159 (17.89), embodiment 160 (18.72), embodiment 161 (19.91), embodiment 162 (17.79), embodiment 179 (4.25), embodiment 180 (11.43), embodiment 181 (12.30), embodiment 182 (12.83), embodiment 183 (10.51), embodiment 184 (12.12), embodiment 185 (10.14), embodiment 186 (10.09), embodiment 187 (10.14), embodiment 188 (10.65), embodiment 189 (10.73), embodiment 190 (10.10), embodiment 191 (10.17), embodiment 192 (10.19), embodiment 193 (11.02), embodiment 194 (9.92), embodiment 195 (10.74), embodiment 196 (9.94).
Embodiment 46 is shown in Table 1.Begin synthetic peptide from amino acid Pro with the resin grafting.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DAsp (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 46 (8.94).
Embodiment 47 is shown in Table 1.Begin the synthetic of peptide from amino acid Asp with the resin grafting.Initial resin is Fmoc-Asp (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Asp (OtBu)- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 47 (7.29).
Embodiment 48 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro (5RPhe).Initial resin is Fmoc-Pro (5RPhe)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Pro (5RPhe)- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 48 (10.07).
Embodiment 49 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DAla-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 49 (8.09);
Embodiment 50 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DIle-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 50 (9.78).
Embodiment 51 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Leu.Initial resin is a Fmoc-Leu-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Leu- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 51 (8.94);
Embodiment 64 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Glu.Initial resin is Fmoc-Glu (OtBut)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Glu (OtBu)- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 64 (13.17).
Embodiment 68 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Asp.Initial resin is Fmoc-Asp (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Asp (OtBu)- DAla-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 68 (12.44).
Embodiment 69 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DAsn (Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 69 (12.97).
Embodiment 72 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DThr (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 72 (13.34).
Embodiment 73 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DIle-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 73 (9.78).
Embodiment 74 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Leu.Initial resin is a Fmoc-Leu-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Leu- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 74 (8.94).
Embodiment 115 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DAsp (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 115 (4.82).
Embodiment 116 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DPhe-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 116 (5.98).
Embodiment 117 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DArg (Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 117 (4.48).
Embodiment 118 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DSer (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 118 (4.73).
Embodiment 119 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DVal-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 119 (5.47).
Embodiment 120 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DPic-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 120 (5.48).
Embodiment 121 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Asp.Initial resin is Fmoc-Asp (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Asp (OtBu)- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 121 (4.56).
Embodiment 122 and 167 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Phe.Initial resin is a Fmoc-Phe-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Phe- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 122 (5.75); 167 (5.75).
Embodiment 123,164,169,170,172,173,175,177 and 178 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Gln.Initial resin is Fmoc-Gln (Trt)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Gln (Trt)- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 123 (4.35), 164 (13.20), 169 (16.81), 170 (14.57), 172 (16.78), 173 (13.57), 175 (15.94), 177 (16.78), 178 (17.45).
Embodiment 124 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Ser.Initial resin is Fmoc-Ser (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Ser (OtBu)- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 124 (4.46).
Embodiment 125 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Val.Initial resin is a Fmoc-Val-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Val- DPro-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 125 (18.42).
Embodiment 126 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Thr.Initial resin is Fmoc-Thr (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Thr (OtBu)- DThr (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 126 (4.35).
Embodiment 127,163,165 and 174 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Glu.Initial resin is Fmoc-Glu (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Glu (OtBu)- DLys (Boc)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 127 (4.11), 163 (14.93), 165 (14.40), 174 (12.73).
Embodiment 128 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Thr.Initial resin is Fmoc-Thr (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Thr (OtBu)- DPhe-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 128 (5.26).
Embodiment 130 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Pro.Initial resin is a Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro- DAla-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 130 (14.79).
Embodiment 166 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Ile.Initial resin is a Fmoc-Ile-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Ile- DPhe-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 166 (16.80).
Embodiment 168 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Asp.Initial resin is Fmoc-Asp (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Asp (OtBu)- DPro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 168 (4.56).
Embodiment 171 and 176 is shown in Table 1.From beginning the synthetic of peptide with resin grafted amino acid Gln.Initial resin is Fmoc-Gln (Trt)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, its be following sequence: resin-Gln (Trt)- DGln (Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, described in program B, form disulfide linkage, downcut peptide, carry out cyclisation, remove protection and purifying from resin.
Use analytical procedure mentioned above, mensuration HPLC-retention time (minute):
Embodiment 171 (15.40), 176 (13.67).
Table 1: embodiment
Embodiment Sequence number ?P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 Template Purity % a) [M+H]
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. SEQ?ID?NO：1 SEQ?ID?NO：2 SEQ?ID?NO：3 SEQ?ID?NO：4 SEQ?ID?NO：5 SEQ?ID?NO：6 SEQ?ID?NO：7 SEQ?ID?NO：8 SEQ?ID?NO：9 SEQ?ID?NO：10 SEQ?ID?NO：11 SEQ?ID?NO：12 SEQ?ID?NO：13 SEQ?ID?NO：14 SEQ?ID?NO：15 SEQ?ID?NO：16 SEQ?ID?NO：17 SEQ?ID?NO：18 SEQ?ID?NO：19 SEQ?ID?NO：20 SEQ?ID?NO：21 SEQ?ID?NO：22 SEQ?ID?NO：23 SEQ?ID?NO：24 SEQ?ID?NO：25 SEQ?ID?NO：26 SEQ?ID?NO：27 SEQ?ID?NO：28 ?Phe?Phe?Phe?Phe?Phe?Tyr?Arg?Arg?4AmPhe?Nle?Chg?Chg?2Cl-Phe?Ile?Phe?Phe?Ile?Ile?Ile?Ile?Phe?Ile?Phe?Phe?Phe?Tyr?hPhe?hPhe Cys Cys Cys Cys Cys Cys Glu Nle Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Nle Nle Lys Lys Lys Lys Lys Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser AlloThr Dpr Ser Ser Ser Glu Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Glu Asp Asp Asp Asp Asp Asp Asp Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Ala Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Nle Cha Gln Tyr Nle Cha Ile Ile Ile Ile Ile Ile Ile Ile Cys Cys Cys Cys Cys Cys Arg Nle Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Thr Asp Ash Ser Tyr Thr Phe Phe Ser Ser Ser Arg Arg Arg Ser Ser Arg Arg Arg Arg Ser Arg Tyr Ser Ser Tyr Asn Thr DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro 95 93 95 95 95 95 95 95 92 93 95 95 95 93 95 95 95 89 95 95 95 95 95 95 95 95 95 95 1385.7 1399.5 1398.5 1371.1 1447.5 1401.7 1521.2 1462.4 1386.9 1337.8 1363.8 1432.7 1474.5 1380.5 1371.8 1411.6 1421.6 1456.6 1476.6 1446.5 1385.8 1391.6 1432.7 1385.7 1370.9 1463.8 1412.6 1399.7
Table 1 is continuous, embodiment
Embodiment Sequence number P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 Template Purity % a) [M+H]
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. SEQ?ID?NO：29 SEQ?ID?NO：30 SEQ?ID?NO：31 SEQ?ID?NO：32 SEQ?ID?NO：33 SEQ?ID?NO：34 SEQ?ID?NO：35 SEQ?ID?NO：36 SEQ?ID?NO：37 SEQ?ID?NO：38 SEQ?ID?NO：39 SEQ?ID?NO：40 SEQ?ID?NO：41 SEQ?ID?NO：42 SEQ?ID?NO：43 SEQ?ID?NO：44 SEQ?ID?NO：45 SEQ?ID?NO：46 SEQ?ID?NO：47 SEQ?ID?NO：48 SEQ?ID?NO：49 SEQ?ID?NO：50 SEQ?ID?NO：51 SEQ?ID?NO：52 SEQ?ID?NO：53 SEQ?ID?NO：54 SEQ?ID?NO：55 SEQ?ID?NO：56 SEQ?ID?NO：57 SEQ?ID?NO：58 SEQ?ID?NO：59 SEQ?ID?NO：60 SFQ?ID?NO：61 hPhe hPhe 4AmPhe 4AmPhe Cha Cha Cha Cha Chg Chg Chg Chg Nle Nle Nle Nle 2Cl-Phe Phe Phe Phe Phe Phe Phe Ile Phe Phe Ile Ile Ile Ile Ile Phe Trp Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Nle Nle Lys Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Ala Pro Pro Pro Pro Pro Pro Pro Pro Pro Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Nle Cha Gln Tyr Nle Cha Ile Ile Ile Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Asp Tyr Asn Tyr Asn Thr Asp Tyr Asn Thr Asp Tyr Asn Thr Asp Tyr Asn Ser Ser Ser Ser Ser Ser Arg Ser Ser Arg Arg Arg Arg Arg Tyr Ser DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DAsp LPro DPro LAsp DPro LPro(5RPhe) DAla LPro DIle LPro DPro LLeu DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro 95 95 91 93 94 95 95 95 95 95 95 95 95 93 95 95 95 95 95 95 95 94 94 93 95 95 95 89 94 95 95 95 95 1413.6 1461.7 1413.8 1462.7 1404.8 1391.7 1405.8 1453.8 1390.7 1377.6 1391.6 1439.6 1364.7 1351.7 1365.7 1413.6 1432.6 1389.6 1389.6 1447.5 1345.6 1387.9 1395.7 1380.7 1371.8 1411.6 1421.6 1456.5 1406.6 1446.5 1391.6 1432.7 1410.9
Table 1 is continuous, embodiment
Embodiment Sequence number P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 Template Purity % a) [M+H]
62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. SEQ?ID?NO：62 SEQ?ID?NO：63 SEQ?ID?NO：64 SEQ?ID?NO：65 SEQ?ID?NO：66 SEQ?ID?NO：67 SEQ?ID?NO：68 SEQ?ID?NO：69 SEQ?ID?NO：70 SEQ?ID?NO：71 SEQ?ID?NO：72 SEQ?ID?NO：73 SEQ?ID?NO：74 SEQ?ID?NO：75 SEQ?ID?NO：76 SEQ?ID?NO：77 SEQ?ID?NO：78 SEQ?ID?NO：79 SEQ?ID?NO：80 SEQ?ID?NO：81 SEQ?ID?NO：82 SEQ?ID?NO：83 SEQ?ID?NO：84 SEQ?ID?NO：85 SEQ?ID?NO：86 SEQ?ID?NO：87 SEQ?ID?NO：88 SEQ?ID?NO：89 SEQ?ID?NO：90 SEQ?ID?NO：91 SEQ?ID?NO：92 SEQ?ID?NO：93 1-Nal Chg Phe Chg Chg Chg Phe Phe 4AmPhe Chg Phe Phe Phe Arg Ile Nle Nle Nle Nle Nle Nle Nle Nle Nle Nle Nle Nle Nle Nle Nle Nle Nle Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Ala Abu Thr Thr Thr Thr Thr Thr Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Ala Thr Abu Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ser Ser Ser Ser Ser AlloThr Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Leu Ile Ile Nle Aoc OctG Cha hLeu Chg t-BuAla Ile Ile Ile Ile Ile Ile Ile Ile Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro(4NHCOPhe) Pro Pro Pro Pro Pro Ile Nle Ile Tyr Cha Tyr Ile Ile Cha Cha Ile Ile Ile Ile Gln Tyr Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Phe Gln Gln Gln Gln Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Ser Tyr Ser Tyr Tyr Tyr Ser Ser Asn Arg Ser Ser Ser Phe Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Phe Gln Arg Ser DPro LPro DPro LPro DPro LGlu DPro LPro DPro LPro DPro LPro DAla LAsp DAsn LPro DPro LPro DPro LPro DThr LPro DIle LPro DProLeu DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro 95 95 95 95 95 95 95 90 92 95 95 94 94 95 95 95 95 95 95 95 95 95 95 95 95 95 95 88 95 95 56 95 1421.9 1439. 1403.8 1489.5 1479.6 1503.6 1363.6 1388.8 1454.5 1472.6 1375.6 1387.9 1387.9 1440.5 1369.3 1434.3 1383.6 1369.8 1397.6 1425.6 1409.5 1383.6 1395.7 1383.6 1340.1 1354.0 1488.6 1388.7 1353.6 1334.5 1362.6 1293.7
Table 1 is continuous, embodiment
Embodiment Sequence number P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 Template Purity % a) [M+H]
94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. SEQ?ID?NO：94 SEQ?ID?NO：95 SEQ?ID?NO：96 SEQ?ID?NO：97 SEQ?ID?NO：98 SEQ?ID?NO：99 SEQ?ID?NO：100 SEQ?ID?NO：101 SEQ?ID?NO：102 SEQ?ID?NO：103 SEQ?ID?NO：104 SEQ?ID?NO：105 SEQ?ID?NO：106 SEQ?ID?NO：107 SEQ?ID?NO：108 SEQ?ID?NO：109 SEQ?ID?NO：110 SEQ?ID?NO：111 SEQ?ID?NO：112 SEQ?ID?NO：113 SEQ?ID?NO：114 SEQ?ID?NO：115 SEQ?ID?NO：116 SEQ?ID?NO：117 SEQ?ID?NO：118 SEQ?ID?NO：119 SEQ?ID?NO：120 SEQ?ID?NO：121 SEQ?ID?NO：122 Nle Nle Nle Nle Nle Aoc hLeu Chg OctG hPhe Nle Nle Nle Nle Nle Nle Nle Nle Nle Nle Ile Nle Nle Nle Nle Nle Nle Nle Nle Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Glu Glu Thr Gln Thr Gln Thr Gln Cys Cys Cys Cys Cys Cys Cys CyS Cys Cys Cys Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile Ile C5al Leu Leu Ile Ile Ile Ile Ile Ile Ile Ile Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Tyr Tyr Gln Gln Gln Gln Gln Gln Gln Gln Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Lys Arg Lys Arg Met Thr Gln Ser Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Nle 2-Nal 2Cl-Phe Cha Phg Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DAsp LPro DPhe LPro DArg LPro DSer LPro DVal LPro DPic LPro DPro LAsp DPro LPhe 95 94 94 95 95 93 95 87 95 95 95 95 95 90 96 95 81 95 85 95 95 95 95 95 95 95 95 95 95 1319.5 1404.0 1387.8 1359.8 1359.9 1397.4 1383.4 1395.6 1425.5 1417.5 1422.8 1450.9 1394.7 1449.8 1397.7 1394.7 1394.6 1380.7 1413.8 1404.7 1404.7 1387.8 1419.9 1428.6 1359.9 1371.8 1383.7 1387.9 1419.9
Table 1 is continuous, embodiment
Embodiment Sequence number P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 Template Purity % a) [M+H]
123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. SEQ?ID?NO：123 SEQ?ID?NO：124 SEQ?ID?NO：125 SEQ?ID?NO：126 SEQ?ID?NO：127 SEQ?ID?NO：128 SEQ?ID?NO：129 SEQ?ID?NO：130 SEQ?ID?NO：131 SEQ?ID?NO：132 SEQ?ID?NO：133 SEQ?ID?NO：134 SEQ?ID?NO：135 SEQ?ID?NO：136 SEQ?ID?NO：137 SEQ?ID?NO：138 SEQ?ID?NO：139 SEQ?ID?NO：140 SEQ?ID?NO：141 SEQ?ID?NO：142 SEQ?ID?NO：143 SEQ?ID?NO：144 SEQ?ID?NO：145 SEQ?ID?NO：146 SEQ?ID?NO：147 SEQ?ID?NO：148 SEQ?ID?NO：149 SEQ?ID?NO：150 SEQ?ID?NO：151 SEQ?ID?NO：152 SEQ?ID?NO：153 SEQ?ID?NO：154 SEQ?ID?NO：155 Nle Nle Nle Nle Nle Nle Nle Nle Nle hPhe Nle hPhe Nle Nle Nle Nle Nle Nle Nle hPhe hPhe Nle OctG hPhe OctG OctG OctG OctG OctG hPhe hPhe OctG hPhe Cys Cys Cys Cys Cys Cys Cys Cys Cys Glu Cys Thr Thr Cys Cys Cys Thr Cys Cys Gln Cys Cys Cys Cys Thr Cys Cys Cys Cys Cys Cys Gln Cys Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ile Ile Ile Ile Ile Ile OctG Ile Ile Ile Cha Ile OctG Ile Ile Ile Cha Chg Cha Ile Ile Ile Ile Ile Ile OctG Ile Cha OctG OctG OctG Ile Cha Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro(4NHCOPhe) Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro(4NHCOPhe) Pro Pro Pro Pro Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Cys Cys Cys Cys Cys Cys Cys Cys Cys Lys Cys Gln Gln Cys Cys Cys Gln Cys Cys Thr Cys Cys Cys Cys Gln Cys Cys Cys Cys Cys Cys Thr Cys Tyr Tyr Tyr Tyr Tyr Tyr Gln Tyr Gln Tyr Gln Tyr Tyr Phg Phe Tyr Tyr Tyr Tyr Tyr Gln 2Cl-Phe Phe Phe Tyr Gln Gln Tyr Gln Phe Gln Tyr Phe DPro LGln DPro LSer DPro LVal DThr LThr DLys LGlu DPhe LThr DPro LPro DAla LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro 95 95 95 95 95 95 91 95 95 95 95 95 88 95 95 95 95 95 95 91 94 94 95 95 95 95 95 95 94 95 95 93 90 1400.6 1359.5 1371.8 1377.4 1433.5 1423.5 1390.4 1343.5 1334.5 1470.6 1440.5 1442.5 1450.7 1339.9 1353.6 1488.6 1434.8 1395.7 1409.5 1406.5 1383.5 1387.8 1409.4 1401.5 1450.9 1446.6 1390.4 1465.6 1565.7 1457.6 1438.5 1450.9 1441.5
Table 1 is continuous, embodiment
Embodiment Sequence number P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 Template Purity % a) [M+H]
156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. SEQ?ID?NO：156 SEQ?ID?NO：157 SEQ?ID?NO：158 SEQ?ID?NO：159 SEQ?ID?NO：160 SEQ?ID?NO：161 SEQ?ID?NO：162 SEQ?ID?NO：163 SEQ?ID?NO：164 SEQ?ID?NO：165 SEQ?ID?NO：166 SEQ?ID?NO：167 SEQ?ID?NO：168 SEQ?ID?NO：169 SEQ?ID?NO：170 SEQ?ID?NO：171 SEQ?ID?NO：172 SEQ?ID?NO：173 SEQ?ID?NO：174 SEQ?ID?NO：175 SEQ?ID?NO：176 SEQ?ID?NO：177 SEQ?ID?NO：178 SEQ?ID?NO：179 SEQ?ID?NO：180 SEQ?ID?NO：181 SEQ?ID?NO：182 SEQ?ID?NO：183 SEQ?ID?NO：184 OctG OctG hPhe OctG OctG hPhe hPhe Nle Nle OctG Nle Nle Nle Nle Nle Nle Nle hPhe hPhe Nle Nle OctG OctG Nle Ile Ile Ile Ile Phe Glu Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Lys Lys Lys Lys Lys Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ile Cha Cha Cha Cha OctG Cha OctG Cha Ile Ile Ile Ile OctG Cha Cha Cha Ile Ile Cha Cha Ile OctG Ile Leu hPhe Cha Tyr Leu Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro(4NHCOPhe) Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro(4NHCOPhe) Pro Pro Pro Pro Pro Pro Pro Pro Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Ile Ile Ile Ile Ile Lys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Tyr Phe Gln Gln Gln Tyr Tyr Tyr Gln Tyr Tyr Tyr Tyr Tyr Tyr Cha Cha Tyr Tyr 2Cl-Phe Gln Tyr Gln Tyr Arg Arg Arg Arg Arg DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DLys LGlu DPro LGln DLys LGlu DPro LIle DPro LPhe DPro LAsp DPro LGln DPro LGln DGln LGln DPro LGln DPro LGln DLys LGlu DPro LGln DGln LGln DPro LGln DPro LGln DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro 95 95 94 93 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 90 94 92 95 91 95 1478.7 1449.8 1422.7 1430.0 1549.6 1473.4 1457.3 1374.4 1405.5 1488.0 1385.6 1419.9 1387.9 1456.5 1440.5 1461.0 1430.6 1448.6 1480.0 1458.5 1555.5 1430.6 1477.6 1369.7 1404.8 1452.6 1444.6 1454.5 1438.6
Table 1 is continuous, embodiment
Embodiment Sequence number P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 Template Purity % a) [M+H]
185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. SEQ?ID?NO：185SEQ?ID?NO：186SEQ?ID?NO：187SEQ?ID?NO：188SEQ?ID?NO：189SEQ?ID?NO：190SEQ?ID?NO：191SEQ?ID?NO：192SEQ?ID?NO：193SEQ?ID?NO：194SEQ?ID?NO：195SEQ?ID?NO：196 Ile Ile Ile Ile Ile Ile Leu Nle Cha Tyr Trp Arg Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Arg Lys His Gln Thr Arg Lys Lys Lys Lys Lys Lys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Cys Arg Arg Arg Arg Arg Lys Arg Arg Arg Arg Arg Tyr DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro DPro LPro 95 95 95 95 95 95 95 95 95 95 92 95 1447.5 1419.9 1428.6 1419.8 1392.4 1420.1 1420.0 1420.0 1459.7 1469.6 1492.6 1469.6
A) the % purity of compound after the preparation property HPLC
Embodiment 1-6,9-103,112-131,133,136-138,140-141,143-146,148-153,155, the 2nd and 10 Cys has formed disulfide linkage among the 157-196.
2. biological method
2.1. preparation peptide sample
As do not have other explanation, the freeze dried peptide of weighing on microbalance (Mettler MT5) is dissolved in it in aqua sterilisa, to final concentration be 1mM.Storage liquid keeps in Dark Place in+4 ℃.
2.2. enzyme test
Enzyme and substrate condition are shown in Table 2.
Carry out in the 96 hole flat undersides (Greiner) of total reaction volume on Genios plate reader (Tecan) of kinetic measurement with 100 μ l.Enzyme and peptide (inhibitor) are merged in damping fluid, and described damping fluid contains 100mM HEPES (pH 7.5), 50mM CaCl 2, 0.025% tween 20,5%DMSO and 1mM substrate.Change the speed of measuring substrate hydrolysis by the 405nm absorbancy of monitoring 30 minutes, with the linearity of confirmatory reaction curve.Be used to all calculating from the 1st minute to the 10th minute mean rate.Use is carried out Background subtraction, mean rate, bipartite average and initial calculation that % suppresses from the Magellan software (the 5th edition) of Tecan.By using Grafit (version 5.0.10) to calculate IC50% from the inhibition data fitting of 6 kinds of different inhibitor concentration in following 4 parameter equatioies from Erithacus Software:
y = 100 % 1 + ( x IC 50 ) s
In this equation, s is a slope coefficient, and x is an inhibitor concentration, and y is that the % of given concentration inhibitor suppresses.
K m/ K iMeasure
Measure the K of serine stretch protein enzyme substrates from Lineweaver-Burke figure (Grafit v5) mUse formula K i=IC50%/(1+ ([substrate]/K m)) calculate the Ki value of inhibitor.
Substrate that concentration increases gradually and enzyme reaction are mapped to concentration of substrate with the speed (ABS/mSec) of each reaction.Also draw figure reciprocal (Lineweaver-Burke), so that K to be provided mAnd V Max(illustration) (described reference 1 vide infra).
Table 2
Enzyme/supplier Enzyme concn in the test Substrate/supplier Concentration of substrate in the test (mM)
Elastoser/Serva from human neutrophil 0.6mU/ reaction N-Met-Ala-Pro-Val-is to p-nitroanilide/Sigma 1
The CAS of cathepsin G numbering 107200-92-0 Calbiochem from human neutrophil The 1mU/ reaction N-succinyl--Ala-Pro-Phe-is to p-nitroanilide Sigma 1
Trypsinase, the iodate level, from human pancreas, CAS numbering 9002-07-7 Calbiochem The 1mU/ reaction N-benzoyl-Arg-is to p-nitroanilide Sigma 0.32
The chyme enzyme, from human skin, Calbiochem The 9mU/ reaction N-succinyl--Ala-Pro-Phe-is to p-nitroanilide Sigma 1.5
Zymoplasm, from human plasma, high reactivity, CAS numbering 9002-044 Calbiochem The 100mU/ reaction Benzoyl-Phe-Val-Arg-is to p-nitroanilide Calbiochem 0.5
Quimotrase, from human pancreas, CAS numbering 9004-07-3 Calbiochem 1.6 little M/ reaction N-succinyl--Ala-Pro-Phe-is to p-nitroanilide Sigma 1
Factor Xa, from human plasma, CAS numbering 9002-05-5 Calbiochem 0.4mU/ reaction Methoxycarbonyl-D-Nle-Gly-Arg-presses Roche to nitro acyl benzene 2
Tryptase is from human lung, Calbiochem 12.5mU/ reaction N-benzoyl-Arg-is to p-nitroanilide Sigma 1.28
Urokinase is numbered 9039-53-6 from human urine/Sigma Aldrih CAS The 250mU/ reaction Pyroglu-Gly-Arg-is to p-nitroanilide xHCl Endotell 0.5
Enzyme/supplier Enzyme concn in the test Substrate/supplier Concentration of substrate in the test (mM)
Kallikrein, from human plasma, CAS numbering 9001-01-8 Calbiochem 0.34 microgram/reaction N-benzoyl-Pro-Phe-Arg-is to p-nitroanilide Sigma 1
Plasmin, from human plasma, CAS numbering 9001-90-5 Sigma-Aldrich The 2mU/ reaction D-Val-Leu-Lys-is to p-nitroanilide Sigma 5
2.3. cell toxicity test
Use MTT reduction test [reference 2 and 3 in seeing below], measure the cytotoxicity of peptide HELA cell (Acc57) and COS-7 cell (CRL-1651).This method is summarized as follows: respectively with every hole 7.0 * 10 3Individual cell and 4.5 * 10 3Individual cell inoculation HELA cell and COS-7 cell, and make them in 96 hole microtiter plates, in 37 ℃, 5%CO 2Under grew 24 hours.At this point, by MTT reduction (seeing below) minute zero point (Tz).Discard the supernatant liquor of residue in the hole, the peptide of fresh culture and 12.5,25 and 50 μ M serial dilutions is inhaled moved on in the hole.Triplicate each peptide concentration of measuring.At 37 ℃, 5%CO 2Continue the incubation 48 hours of cell down.Use phosphate buffered saline (PBS) (PBS) hole flushing then, in the hole, add 100 μ l MTT reagent (0.5mg/ml is respectively in RPMI1640 and DMEM substratum) subsequently.This was 37 ℃ of incubations 2 hours, and the sucking-off substratum adds 100 μ l Virahols in each hole subsequently.Measure the absorbancy (OD of dissolved product at the 595nm place 595Peptide).For each concentration, all come calculating mean value from triplicate measured value.The growth percentage calculation is as follows: (OD 595Peptide-OD 595Tz-OD 595Emptying aperture)/(OD 595Tz-OD 595Emptying aperture) * 100%, it is mapped to each peptide concentration.
Use (50,25,12.5 grow the accordingly Trendline function of EXCEL (Microsoft Office 2000) of per-cent and value-50 and 0 μ m),, (=TREND (C50: C0, %50: %0,-50)), measure the LC50 value (lethal concentration is defined as killing the concentration of 50% cell) of every kind of peptide.
By working concentration (50,25,12.5 and 0 μ g/ml), the Trendline function of corresponding percentage and value 50, (TREND (C 50: C 0, % 50: ‰, 50)), calculate GI50 (growth-inhibiting) concentration of every kind of peptide.
2.4. haemolysis
Peptide is tested their hemolytic activities at human erythrocyte (hRBC).By centrifugal 10 minutes, fresh hRBC is given a baby a bath on the third day after its birth time with phosphate buffered saline (PBS) (PBS) at 2000 * g.With concentration is the peptide of 100 μ M and 20%v/v hRBC 37 ℃ of incubations 1 hour.Final red blood cell concentration is approximately every milliliter 0.9 * 10 9Individual cell.By having only PBS and having H respectively 2Incubation hRBC under the situation of 0.1%Triton X-100 among the O measures the value of 0% and 100% lysis respectively.Sample is carried out centrifugal, in the PBS damping fluid, supernatant liquor is carried out 20 times of dilutions, measure the optical density(OD) (OD) of 540nM place sample.100% cracking value (OD 540H 2O) provided the OD of about 1.3-1.8 540Per-cent haemolysis is calculated as: (OD 540Peptide/OD 540H 2O) * 100%.
2.5 plasma stability
405 μ l blood plasma/albumin solns are put into polypropylene (PP) pipe, with 45 μ l compound fusion from 100mM solution B (obtaining) by the peptide among the PBS of 135 μ l PBS and 15 μ l 1mM pH 7.4.The five equilibrium sample of 150 μ l is transferred in each hole of 10kDa screen plate (MilliporeMAPPB 1010 Biomax films).For " contrast in 0 minute ", 270 μ lPBS are put into the PP pipe, add 30 μ l storage liquid B, concussion mixes.150 μ l contrast solutions are put into a hole of screen plate and are used as " filtered contrast ".
Other gets 150 μ l contrast solutions, directly puts into receiver hole (for filtrate is reserved), as " contrast of filtered ".The whole plate that comprises evaporation lid was 37 ℃ of incubations 60 minutes.4300rpm (3500g) and 15 ℃ to plasma sample (rat plasma: Harlan Sera laboratory, UK; Human plasma: Blutspendezentrum Z ü rich) centrifugal at least 2 hours, to produce 100 μ l filtrates.For " plasma-albumin " sample (human white protein of prepared fresh: SigmaA-4327; The rat white protein: Sigma A-6272, concentration all is the 40mg/ml among the PBS), about 1 hour is centrifugal just enough.According to hereinafter described, by LC/MS the filtrate in the PP plate that receives usefulness is analyzed: post: Jupiter C18 (Phenomenex), moving phase: (A) 0.1% formic acid and (B) acetonitrile in the water, gradient: 5%-100% in 2 minutes (B), electro-spray ionization, MRM surveys (triple quadrupole).Measure the area at peak, and in addition average to the value of triplicate mensuration.In conjunction with (time point of filtered and filtered 0 minute) contrast 1 and contrast 2:100-(100 * T 60/ T 0) percentage recently represent.Calculate the mean value of these values then.
2.6. pharmacokinetic study (PK)
Pharmacokinetic study after single oral in the rat (tube feed) and intravenously are used
The compound of embodiment 75 (" Ex.75 ") has been carried out single intravenously (i.v.) and per os (p.o., the tube feed) pharmacokinetic study after using.Use from RCC Ltd laboratory animal portion, CH-4414 F ü llinsdorf, the 332g that Switzerland obtains (± 10g) male Wistar mouse in the research.Add medium physiological saline, make that the compound final concentration is 2.5mg/ml.It is 2ml/kg that intravenously is used volume, is 10ml/kg for the dosage forms for oral administration volume, and the peptide of injection embodiment 75 provides the final intravenous dosages of 5mg/kg and the oral dosage of 50mg/kg.According to scheme hereinafter described, at different time points, use DiLab AccuSampler by automatic blood specimen collection, (approximately 0.24ml) is taken in the pipe of heparinization with blood sample.At following point in time sampling: 0,5 minutes (only intravenously), 15,30 minutes and 1,2,4,8,16,24 and 36 (only per os) hour, and join in the pipe of heparinization.Blood plasma is shifted out from sedimentary cell in centrifugal back, is frozen in-80 ℃ before HPLC-MS analyzes.
Preparation blood plasma correcting sample
Use is from " blank " rat plasma of undressed animal.With the five equilibrium sample of blood of every part of 0.1ml slurry and 50ng Proprasylyte (interior mark, IS), (by at OASIS Carry out solid phase extractions on the HLB cartridge case (Waters) and prepare sample) and the peptide of the embodiment 75 of known quantity mix, be 9 parts of blood plasma correcting samples between the 5-2000ng/ml with the acquisition scope.Use 1ml methyl alcohol, again the 1ml 1%NH in the water 3Regulate OASIS Last HLB cartridge case.400 μ l 1%NH in the water then 3Dilute sample, and go up sample.1ml methyl alcohol/1%NH in the water 3(5/95) washes plate.Use the 1ml 0.1%TFA in the methyl alcohol to carry out wash-out.
The plate that will contain eluate is introduced the thickener system, makes its drying.Resistates is dissolved among 100 μ l formic acid, 0.1%/acetonitrile, 95/5 (v/v), and uses gradient elution (mobile phase A: 0.1% formic acid in the water; B: acetonitrile, in 2 minutes from 5%B to 100%B), (5 μ m Phenomenex) go up and to analyze in HPLC/MS for Jupiter C18,50 * 2.0mm at anti-phase analytical column.
The preparation plasma sample
Getting 100 μ l blood plasma from every duplicate samples is used for extracting.Less than 100 μ l, add " blank " mice plasma of appropriate amount as fruit volume so, to keep matrix identical with calibration curve.Then with sample and IS fusion, according to handling about calibration curve is described.
Pharmacokinetics is estimated
Use software PK solution 2.0 TM(Summit Research Service, Montrose, CO 81401 USA) carry out PK to the data (n=2 or 3 usually) of collecting and analyze.Come area A UC under the calculated curve by the trapezoidal law of linearity.With AUC (t-∞)Be estimated as Ct/b (b: elimination rate constant).AUC (t-∞)Be AUC (0-t)And AUC (t-∞)And.Calculate the removing transformation period by the linear regression at least three data points of the phase of elimination.By relation conefficient (r 2) assess the transformation period and measure the selected timed interval, relation conefficient should be at least greater than 0.85 and optimum greater than 0.96.Under the situation that intravenously is used,, determine t by from beginning most two time points with curve extrapolation ZeroThe time initial concentration.At last, by by the AUC that uses with respect to intravenously after normalized intraperitoneal is used (0-∞)Ratio calculates intraperitoneal and uses bioavailability afterwards.
3.0 result
Above the described result of experiment of 2.2-2.5 is showed in hereinafter in the table 3.
Table 3
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase 100 μ M % Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M % FXa 100μM ％ Urokinase 100 μ M % Tryptase 100 μ M % Cytotoxicity LC 50/GI 50The Hela cell Haemolysis 100 μ M %
1 ?86 ＞100000 92.6 7.8 0 1.1 5.7 5.7 0 ?nd 0
2 ?84 ＞100000 92 2.9 0 9.2 5.3 0.9 39.6 ?nd nd
3 ?51 ＞100000 92 0 1 0 4 4 68 ?100 0
4 ?91 ＞100000 96 1.8 0 0 2.4 5.4 0 ?100 0
5 ?56 ＞100000 92 3 0 0.5 0.2 5.7 74 ?nd 0
6 ?？ nd nd nd nd nd nd nd nd ?nd nd
7 ?91 15，100μM％ 41 12 13.4 0 11.7 1.1 1.5 ?100 0.2
8 ?126 0.8，100μM％ 74.2 5.6 71.7 nd nd nd nd ?nd nd
9 ?105 4.1，100μM％ 88.1 nd nd nd nd nd nd ?nd nd
10 ?75 0.3，100μM％ 89.9 nd 9.4 nd nd nd nd ?nd nd
11 ?95 19，100μM％ 65 73.6 12.1 nd nd nd nd ?nd nd
12 ?90 37038 97 28 12 11 5 12 59.3 ?59.3 nd
13 ?100 8.2，100μM％ 95.0 nd 19.9 nd nd nd nd ?nd nd
14 ?52 ＞100000 88 0 42.3 8.7 6 5.4 84.2 ?100 0
15 ?56.0 ＞100000 95.0 54.2 12.7 nd nd nd nd ?100 0
16 ?66 ＞100000 90.0 17.9 12.9 nd nd 3.2 nd ?94 0.1
Table 3 is continuous
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase 100 μ M % Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M% FXa100μM％ Urokinase 100 μ M% Tryptase 100 μ M % Cytotoxicity LC 50/GI 50The Helaz cell Haemolysis 100 μ M%
17 ?55 ＞100000 90.0 16 27.6 0 nd nd 90.4 ?94 0.1
18 ?47 ＞100000 84 25 32.5 0 nd nd 88.3 ?100 0
19 ?41 ＞100000 94.0 0 26.9 11 32 4 85.2 ?100 0
20 ?48 ＞100000 97.0 0 44.1 28 25 6.7 nd ?100 0
21 ?97 16.4 95.6 2.6 5 nd nd nd nd ?nd nd
22 ?55 ＞100000 84. 0 98.8 nd nd 5.7 3.8 ?8 0
23 ?38 ＞100000 90 4 60 0 11 9 29 ?51 0
24 ?71 ＞100000 97 1.0 1.2 3.5 30 5.1 0 ?99 nd
25 ?102 3.2，100μM％ 89.3 nd 10.0 nd nd nd nd ?nd nd
26 ?49 ＞100000 84 2.2 0 3 6 3.1 66.4 ?nd nd
27 ?48 nd nd nd nd nd nd nd nd ?nd nd
28 ?39 ＞100000 95 32 0 12 6 1 0 ?nd nd
29 ?42 nd nd nd nd nd nd nd nd ?nd nd
30 ?39 49900 98 49 0 2 3 9 nd ?nd nd
31 ?34 ＞100000 98 15 12 10 8 15 76 ?nd nd
32 ?52 nd nd nd nd nd nd nd nd ?nd nd
33 ?45 nd nd nd nd nd nd nd nd ?nd nd
34 ?56 nd nd nd nd nd nd nd nd ?nd nd
35 ?54 nd nd nd nd nd nd nd nd ?nd nd
Table 3 is continuous
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase 100 μ M % Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M% FXa 100μM％ Urokinase 100 μ M % Tryptase 100 μ M % Cytotoxicity LC 50/GI 50The Hela cell Haemolysis 100 μ M %
36 ?41 nd Nd nd nd nd nd 0 73.3 ?83 0
37 ?35 nd nd nd nd nd nd 5 56 ?92 0.1
38 ?31 ＞100000 96 4 1 0 0 1 11 ?100 0
39 ?38 ＞100000 94 7 0 2 0 2 34 ?98 0
40 ?25 ＞44862 94 19 8 1 3 10 33 ?97 0.1
41 ?49 nd nd nd nd nd nd nd nd ?nd nd
42 ?46 nd nd nd nd nd nd 7 0 ?87 0
43 ?77 nd nd nd nd nd nd nd nd ?nd nd
44 ?31 ＞10000 100 24 3 9 9 14 50 ?67 0.1
45 ?47 nd nd nd nd nd nd nd nd ?nd nd
46 ?87.5 ＞100000 95 0 10.2 6.9 12.2 5.8 44.1 ?nd nd
47 ?64 ＞10000 87 1 8.2 0 9.3 6.3 0 ?100 0
48 ?83 ＞100000 93 3 nd nd nd nd nd ?nd nd
49 ?82 ＞10000 96 0 0 7.9 nd 6.2 30.5 ?nd nd
50 ?89 ＞100000 94 0 nd nd nd nd nd ?nd nd
51 ?91 ＞100000 nd nd nd nd nd nd nd ?nd nd
52 ?52 ＞100000 86 0 42.3 8.7 6 5.4 84.2 ?100 0
53 ?56 ＞100000 95 54 12.7 nd nd nd nd ?63 0
54 ?66 ＞100000 90 18 12.9 nd nd 3.2 nd ?nd nd
55 ?55 ＞100000 90 16 27.6 nd nd nd 90.4 ?94 0.1
56 ?47 ＞100000 84 25 32.5 0 nd nd 88.3 ?100 0
Table 3 is continuous
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase 100 μ M % Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M% FXa100μM％ Urokinase 100 μ M % Tryptase 100 μ M % Cytotoxicity LC 50/GI 50The Hela cell Haemolysis 100 μ M%
57 ?41 ＞100000 94 0 26.9 11 32 4 82.2 ?0 0
58 ?475 ＞100000 97 0 44.1 28 25 6.7 nd ?100 0
59 ?55 ＞100000 84 0 98.8 nd nd 5.7 3.8 ?8 0
60 ?38 ＞100000 90 4 60 0 11 9 29.4 ?51 0
61 ?72 nd nd nd nd nd nd nd nd ?nd nd
62 ?69 nd nd nd nd nd nd nd nd ?nd nd
63 ?41 ＞100000 96 11 7 1 0 0 50 ?87 0
64 ?45 ＞100000 87 0 0 2.3 0 3 0 ?59 0
65 ?47 nd nd nd nd nd nd 1 57 ?84 0
66 ?48 nd nd nd nd nd nd nd nd ?nd nd
67 ?48 nd nd nd nd nd nd nd nd ?nd nd
68 ?59 ＞100000 84.2 4.3 0 5.4 8.6 4.6 21.3 ?nd nd
69 ?68 nd nd nd nd nd nd nd nd ?nd nd
70 ?69 nd nd nd nd nd nd nd nd ?nd nd
71 ?70 nd nd nd nd nd nd nd nd ?nd nd
72 ?87 nd nd nd nd nd nd nd nd ?nd nd
73 ?89 ＞100000 94 0 nd nd nd nd nd ?nd Nd
74 ?91 ＞100000 86 ＞100000 nd nd nd nd nd ?nd nd
75 ?86 69.1，100μM％ 92.6 7.8，100μM％ 0 1.1 5.7 5.7 0 ?nd nd
76 ?nd 71 nd nd nd nd nd nd nd ?nd nd
Table 3 is continuous
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase 100 μ M % Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M% FXa 100μM％ Urokinase 100 μ M % Tryptase 100 μ M % Cytotoxicity LC 50/GI 50The Hela cell Haemolysis 100 μ M %
77 nd 68 nd nd nd nd nd nd nd nd nd
78 nd 29 nd ＜4000 nd nd nd nd nd 61 nd
79 nd 66 nd nd nd nd nd nd nd nd nd
80 nd 35 nd ＞20000 nd nd nd nd nd 12 nd
81 61.3，100μM％ 28 100000 100000 nd 13.1 8.7 nd nd 58 nd
82 nd 18 nd 72.9 nd nd 15.3 nd 44.5 nd nd
83 nd 43 nd 100000 nd nd nd nd nd 12 nd
84 20195 18 10.8 17103 0 20.6 13.3 10.4 4.2 9 nd
85 nd 28 0 ＞20000 nd 12.6 25.6 nd nd nd nd
86 47，100μM％ 26 0 ＞100000 0 10.7 24.8 nd 0 nd nd
87 nd 37 nd 106977 nd nd nd nd nd 65 nd
88 ＞100000 18 6.4 4309 0 0.2 3 96 0.6 73 nd
89 nd 43 nd nd nd nd nd nd nd 51 nd
90 66975 21 5.2 33074 0 0 5.5 3.5 5 96 nd
91 45，100μM％ 28 0 48108 4.7 13.5 19.4 nd nd 79 nd
92 nd 43 nd nd nd nd nd nd nd 93 nd
93 nd 41 nd nd nd nd nd nd 5.6 100 nd
94 nd 50 nd nd nd nd nd nd nd nd nd
95 38677 24 8.9 33729 0 0 11.3 10.3 0 89 nd
Table 3 is continuous
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase 100 μ M % Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M% FXa100μM％ Urokinase 100 μ M % Tryptase 100 μ M % Cytotoxicity LC 50/GI 50The Hela cell Haemolysis 100 μ M%
96 21175 15 75 15433 0 3.6 0 6.2 0 ?52 nd
97 ＞100000 24 9.5 77431 0 11.6 4.8 11.9 0 ?100 nd
98 ＞100000 21 0 38820 0 5.2 0 0 0 ?78 nd
99 85196 16 30.5 8558 0 0 0 17.4 0 ?58 nd
100 nd 35 nd nd nd nd nd nd nd ?83 nd
101 nd 49 nd nd nd nd nd nd nd ?nd nd
102 ＞100000 13 0 4975 0 1.7 0 0.5 0 ?55 nd
103 ＞100000 18 6.4 4309 0 10.2 3 9.6 0.6 ?47 nd
104 53.5，100μM％ 34 0 3.1，100μM％ 0 7.7 6.2 0 0 ?nd nd
105 nd 34 nd nd nd nd nd nd nd ?nd nd
106 nd 49 nd nd nd nd nd nd nd ?nd nd
107 nd 51 nd nd nd nd nd nd nd ?nd nd
108 nd 31 nd nd nd nd nd nd nd ?nd nd
109 54.1，100μM％ 33 0 13.8 0.1 0 5.6 nd nd ?nd nd
110 nd 38 nd nd nd nd nd nd nd ?nd nd
111 nd 46 nd nd nd nd nd nd nd ?nd nd
112 nd 39 nd nd nd nd nd nd nd ?33 nd
113 nd 35 nd nd nd nd nd nd nd ?nd nd
114 nd 47 nd nd nd nd nd nd nd ?34 nd
115 nd 38 nd 27751 nd nd nd nd nd ?51 nd
116 nd 46 0 39710 nd nd nd nd nd ?nd nd
117 nd 33 nd nd nd nd nd nd nd ?29 nd
118 nd 43 nd nd nd nd nd nd nd ?nd nd
119 nd 45 nd nd nd nd nd nd nd ?nd nd
Table 3 is continuous
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase 100 μ M % Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M% FXa 100μM％ Urokinase 100 μ M % Tryptase 100 μ M% Cytotoxicity LC 50/GI 50The Hela cell Haemolysis 100 μ M%
120 nd 29 nd nd nd nd nd nd nd 38 nd
121 11155 18 12.8 27526，IC50(nmol) 1.2 0 5.6 5.7 4.6 49 nd
122 35134 18 19 58000，IC50(nmol) 6.4 0 19.6 11.1 0.2 29 nd
123 35203 14 7.9 14995，IC50(nmol) 0 2.7 0 7.6 nd nd nd
124 nd 40 nd nd nd nd nd nd nd 40 nd
125 18269 15 28.3 ＞20000，IC50(nmol) 4.8 0 0 nd nd 37 nd
126 nd 36 nd nd nd nd nd nd nd nd nd
127 64，100μM％ 29 0 47.2 1.9 3.7 13.3 nd 0 nd nd
128 nd 40 nd nd nd nd nd nd nd nd nd
129 nd 30 nd nd nd nd nd nd nd nd nd
130 nd 29 nd nd ＜4000 nd nd nd nd nd nd
131 45 28 0 nd 46108 nd nd nd nd nd nd
132 nd 26 nd nd nd nd nd nd nd nd nd
133 nd 26 nd nd nd nd nd nd nd nd nd
134 nd 23 nd nd nd nd nd nd nd nd nd
135 nd 23 nd nd nd nd nd nd nd nd nd
136 ＞100000 21 0 67.9 0 5.2 0 0 0 nd nd
137 66975 21 5.2 68.7 0 0 5.5 3.5 5 nd nd
138 43856 19 12.2 77.1 4.6 17.1 12.6 14.4 0 nd nd
139 nd 18 nd nd nd nd nd nd nd nd nd
Table 3 is continuous
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase 100 μ M % Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M% FXa100μM％ Clotogen 100 μ M % Tryptase 100 μ M% Cytotoxicity LC 50/GI 50The Hela cell Haemolysis 100 μ M%
140 20195 18 10.8 79.6 0 20.6 13.3 10.4 4.2 ?nd nd
141 63.4，100μM％ 18 0 72.9 0 0 15.3 nd 44.5 ?56 nd
142 nd 16 nd nd nd nd nd nd nd ?nd nd
143 28，100μM％ ?15 12 91 0 12 0 8 18 ?nd nd
144 21175 7.5 7.5 80.6 0 3.6 0 6.2 0 ?nd nd
145 nd 14 nd nd nd nd nd nd nd ?nd nd
146 1，100μM％ 12 3 87 0 11 1 0 22 ?nd nd
147 nd 11 nd nd nd nd nd nd nd ?nd nd
148 52，100μM％ 11 9 91 7 32 8 12 30 ?nd nd
149 nd 11 nd nd nd nd nd nd nd ?nd nd
150 nd 10 nd nd nd nd nd nd nd ?nd nd
151 nd 10 nd nd nd nd nd nd nd ?nd nd
152 nd 9 nd nd nd nd nd nd nd ?nd nd
153 56，100μM％ 8.5 8 84 0 16 11 16 9 ?nd nd
154 27，100μM％ 8.3 0 4 0 7 0 1 15 ?nd nd
155 52，100μM％ 8.2 18 83 3 19 9 12 30 ?nd nd
156 46，100μM％ 7.5 0 5 0 17 0 7 15 ?nd nd
157 nd 7 nd nd nd nd nd nd nd ?nd nd
158 55，100μM％ 7.1 8 93 0 2 1 10 13 ?nd nd
159 nd 7 nd nd nd nd nd nd nd ?nd nd
160 55，100μM％ 6 3 94 2 23 1 14 30 ?nd nd
161 nd 6 nd nd nd nd nd nd nd ?nd nd
162 nd 12.5 nd nd nd nd nd nd nd ?nd nd
163 nd 24 nd nd nd nd nd nd nd ?nd nd
Table 3 is continuous
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase 100 μ M% Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M% FXa 100μM％ Urokinase 100 μ M % Tryptase 100 μ M% Cytotoxicity LC 50/GI 50The Hela cell Haemolysis 100 μ M%
164 nd 24 nd nd nd nd nd nd nd ?nd nd
165 nd 22 nd nd nd nd nd nd nd ?nd nd
166 nd 18 nd nd nd nd nd nd nd ?nd nd
167 35134 18 19 60.2 6.4 0 19.6 11.1 0.2 ?nd nd
168 11155 18 12.8 72.9 1.2 0 5.6 5.7 4.6 ?nd nd
169 20295 18 10.8 79.6 0 20.6 133 10.4 4.2 ?nd nd
170 nd 16 nd nd nd nd nd nd nd ?nd nd
171 nd 13 nd nd nd nd nd nd nd ?nd nd
172 nd 13 nd nd nd nd nd nd nd ?nd nd
173 nd 12 nd nd nd nd nd nd nd ?nd nd
174 56，100μM％ 12 7 85 0 11 3 1 10 ?nd nd
175 nd 12 nd nd nd nd nd nd nd ?nd nd
176 69，100μM％ 103 7 55 2 15 1 8 17 ?nd nd
177 54，100μM％ 7 5 86 3 17 7 12 15 ?nd nd
178 nd 6 nd nd nd nd nd nd nd ?nd nd
179 nd 50 ＞100000，IC50(nmol) 76.0 nd nd nd nd 0 ?nd nd
Table 3 is continuous
Embodiment The IC50 of cathepsin G (nmol) Elastoser IC50 (nmol) Trypsinase IC50100 μ M % Quimotrase 100 μ M% Chyme enzyme 100 μ M % Zymoplasm 100 μ M% FXa 100μM％ Urokinase 100 μ M % Tryptase IC50 (nmol) Cytotoxicity LC 50/GI 50The Hela cell Haemolysis 100 μ M %
180 120 nd 60 nd nd nd nd nd ＜100 ?nd nd
181 127 nd 113 nd nd nd nd nd 40 ?nd nd
182 111 nd 59 nd nd nd nd nd 39 ?nd nd
183 243 nd 146 nd nd nd nd nd 25 ?nd nd
184 221 nd 48 nd nd nd nd nd 27 ?nd nd
185 514 nd 126 nd nd nd nd nd 14 ?nd nd
186 337 nd 99 nd nd nd nd nd 15 ?nd nd
187 158 nd 39 nd nd nd nd nd ＜100 ?nd nd
188 105 nd 34 nd nd nd nd nd ＜100 ?nd nd
189 164 nd 39 nd nd nd nd nd ＜100 ?nd nd
190 1500 nd 172 nd nd nd nd nd ＜100 ?nd nd
191 400 nd 66 nd nd nd nd nd 21 ?nd nd
192 650 nd 72 nd nd nd nd nd 16 ?nd nd
193 431 nd 35 nd nd nd nd nd 6 ?nd nd
194 1570 nd 431 nd nd nd nd nd 9 ?nd nd
195 4000 nd 108 nd nd nd nd nd 12 ?nd nd
196 2165 nd 70 nd nd nd nd nd 52 ?nd nd
Nd: do not survey and form sediment
Above result of experiment described in 2.5 hereinafter has been shown in the table 4.
Table 4
Embodiment Stability, human plasma t 1/2(minute) Stability, rat plasma t 1/2(minute)
22 300 300
23 300 300
75 300 300
121 300 300
158 300 300
The above described result of experiment of 2.6 (PK) hereinafter has been shown in the table 5.
Table 5
Route of administration Intravenously Per os
Dosage (mg/kg) 5 50
Dosage Normalized(mg/kg) 5 5
AUC? 0-t(ng·h/ml) 6044 782
AUC? 0-∞(ng·h/ml) 6047 813
AUC? 0-∞ is normalized(ng·h/ml) 6047 81
T Max is observed(hour) 10752 464
T Max is normalized(hour) 10752 46
C Max is normalized(ng/ml) 0.08 0.25
β (hour -1)
Terminal t 1/2(hour) 0.5 0.87
Vd(ml/kg) 547 1008
% absorbs (F) (normalized AUC 0-∞-(per os) is to normalized AUC 0-∞The per-cent of (intravenously)) 100％ 1.3％
After single oral was used, significantly (intravenously was used %C.V=6-68% to the big interindividual variation of the peptide plasma concentration of embodiment 75, except a value 173% when the minimum survey concentration; Dosage forms for oral administration %C.V.:113-173%).
Intravenously is used
After using the peptide of embodiment 75 with the dosage level intravenously of 5mg/kg body weight, the peptide of embodiment 75 is followed the intravenously dynamic characteristic.After PK analyzed, the peptide of embodiment 75 showed, the C of extrapolation InitialBe 14069ng/ml, observed C when 5 minutes (0.083 hour) MaxBe 10762ng/ml.Blood plasma level is dropped rapidly to 5774 and 3455ng/ml respectively when 15 minutes and 30 minutes.From 1 to 2 hour, blood plasma level was with 0.46 hour terminal t 1/218ng/ml when being reduced to 4 hours.AUC 0tAnd AUC 0-∞Be respectively 6044 and 6047ngxh/ml, initial distribution volume is 355ml/kg.Apparent volume of distribution is 547ml/kg.
Dosage forms for oral administration
After the peptide with the dosage level dosage forms for oral administration embodiment 75 of 50mg/kg body weight, the blood plasma level of the peptide of embodiment 75 is followed the dynamic characteristic of dosage forms for oral administration.After PK analyzed, the peptide of embodiment 75 showed, observed C when 0.25 hour (15 minutes) MaxBe 464ng/ml.From 0.25 hour, blood plasma level was with 0.87 hour terminal t 1/224ng/ml when being reduced to 4 hours.AUC 0-tAnd AUC 0-∞Be respectively 782 and 813ngxh/ml.Consider 1.3% absorption, apparent volume of distribution is 1008ml/kg.
The comparison that dosage forms for oral administration and intravenously are used
Because the dosage forms for oral administration group is different with the dosage level that intravenously is used group, after dosage normalization method value is compared.
Use the normalized afterwards AUC of peptide (100%:6047ng-h/ml) of embodiment 75 than intravenously 0-∞The per-cent (F) of the peptide of the embodiment 75 that absorbs after the value, dosage forms for oral administration is 1.3% (81ngxh/ml), normalized C after the dosage forms for oral administration MaxLow about 234 times (the 46 couples of 10762ng/ml of value; Table 3).High about 1.8 times (1008 couples of 547ml/kg) after apparent volume of distribution after the dosage forms for oral administration is used than intravenously.
Reference
1.Barrtt，A.J.Methods?in?Enzymology?1981，80，561-565；Leatherbarrow，R.J.1992，GraFit，Erithacus?Software?Ltd.，Staines，U.K.
2.Mossman?T.J.Immunol.Meth.1983，65：55-63
3.Berridge?MV，Tan?AS.Arch.Biochem.Biophys.1993，303：474-482

Claims (62)

1. the compound of following general formula, and their pharmacy acceptable salt,
Figure A2005800491410002C1
Wherein
Figure A2005800491410002C2
Be the group of one of following formula:
Figure A2005800491410002C3
Figure A2005800491410002C4
Figure A2005800491410002C5
Figure A2005800491410003C1
Figure A2005800491410004C1
Wherein
Figure A2005800491410004C2
Be Gly, or the residue of L-a-amino acid, B is formula-NR 20CH (R 71)-the residue or the enantiomer of one of A1 to the A69 group of definition hereinafter;
Figure A2005800491410004C3
Be the group of one of following formula:
Figure A2005800491410004C4
Figure A2005800491410004C5
Figure A2005800491410004C6
Figure A2005800491410005C1
Figure A2005800491410006C1
Figure A2005800491410007C1
R 1Be H, low alkyl group or aryl lower alkyl;
R 2Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 3Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 4Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(H 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 5Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 6Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 7Be alkyl, thiazolinyl ,-(CH 2) q(CHR 61) sOR 55,-(CH 2) q(CHR 61) sNR 33R 34,-(CH 2) q(CHR 61) sOCONR 33R 75,-(CH 2) q(CHR 61) sNR 20CONR 33R 82,-(CH 2) r(CHR 61) sCOOR 57,-(CH 2) r(CHR 61) sCONR 58R 59,-(CH 2) r(CHR 61) sPO (OR 60) 2,-(CH 2) r(CHR 61) sSO 2R 62Or-(CH 2) r(CHR 61) sC 6H 4R 8
R 8Be H, Cl, F, CF 3, NO 2, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) NR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sCOR 64
R 9Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 10Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 11Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 12Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) r(CHR 61) sCOOR 57,-(CH 2) r(CHR 61) sCONR 58R 59,-(CH 2) r(CHR 61) sPO (OR 60) 2,-(CH 2) r(CHR 61) sSO 2R 62Or-(CH 2) r(CHR 61) sC 6H 4R 8
R 13Be alkyl, thiazolinyl ,-(CH 2) q(CHR 61) sOR 55,-(CH 2) q(CHR 61) sSR 56,-(CH 2) q(CHR 61) sNR 33R 34,-(CH 2) q(CHR 61) sOCONR 33R 75,-(CH 2) q(CHR 61) sNR 20CONR 33R 82,-(CH 2) q(CHR 61) sCOOR 57,-(CH 2) q(CHR 61) sCONR 58R 59,-(CH 2) q(CHR 61) sPO (OR 60) 2,-(CH 2) q(CHR 61) sSO 2R 62Or-(CH 2) q(CHR 61) sC 6H 4R 8
R 14Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) q(CHR 61) sCOOR 57,-(CH 2) q(CHR 61) sCONR 58R 59,-(CH 2) q(CHR 61) sPO (OR 60) 2,-(CH 2) q(CHR 61) sSOR 62Or-(CH 2) q(CHR 61) sC 6H 4R 8
R 15Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 16Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 17Be alkyl, thiazolinyl ,-(CH 2) q(CHR 61) sOR 55,-(CH 2) q(CHR 61) sSR 56,-(CH 2) q(CHR 61) sNR 33R 34,-(CH 2) q(CHR 61) sOCONR 33R 75,-(CH 2) q(CHR 61) sNR 20CONR 33R 82,-(CH 2) q(CHR 61) sCOOR 57,-(CH 2) q(CHR 61) sCONR 58R 59,-(CH 2) q(CHR 61) sPO (OR 60) 2,-(CH 2) q(CHR 61) sSO 2R 62Or-(CH 2) q(CHR 61) sC 6H 4R 8
R 18Be alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sSR 56,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 19Be low alkyl group ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sSR 56,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8Perhaps
R 18And R 19Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 20Be H, alkyl, thiazolinyl or aryl lower alkyl;
R 21Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 22Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 23Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 24Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 25Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 26Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8Perhaps
R 25And R 26Can form together :-(CH 2) 2-6-,-(CH 2) rO (CH 2) r-,-(CH 2) rS (CH 2) r-or-(CH 2) rNR 57(CH 2) r-;
R 27Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 28Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) s-OR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 29Be alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 30Be H, alkyl, thiazolinyl or aryl lower alkyl.
R 31Be H, alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 32Be H, low alkyl group or aryl lower alkyl;
R 33Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 34R 63,-(CH 2) m(CHR 61) sOCONR 75R 82,-(CH 2) m(CHR 61) sNR 20CONR 78R 82,-(CH 2) o(CHR 61) sCOR 64,-(CH 2) o(CHR 61) s-CONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 34Be H, low alkyl group, aryl or aryl lower alkyl;
R 33And R 34Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 35Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) p(CHR 61) sC 6H 4R 8
R 36Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) p(CHR 61) sCOOR 57,-(CH 2) p(CHR 61) sCONR 58R 59,-(CH 2) p(CHR 61) sPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 37Be H, F, Br, Cl, NO 2, CF 3, low alkyl group ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 38Be H, F, Br, Cl, NO 2, CF 3, alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 39Be H, alkyl, thiazolinyl or aryl lower alkyl;
R 40Be H, alkyl, thiazolinyl or aryl lower alkyl;
R 41Be H, F, Br, Cl, NO 2, CF 3, alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 42Be H, F, Br, Cl, NO 2, CF 3, alkyl, thiazolinyl ,-(CH 2) p(CHR 61) sOR 55,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 43Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) sPO (OR 60) 2,-(CH 2) o(CHR 61) sSO 2R 62Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 44Be alkyl, thiazolinyl ,-(CH 2) r(CHR 61) sOR 55,-(CH 2) r(CHR 61) sSR 56,-(CH 2) r(CHR 61) sNR 33R 34,-(CH 2) r(CHR 61) sOCONR 33R 75,-(CH 2) r(CHR 61) sNR 20CONR 33R 82,-(CH 2) r(CHR 61) sCOOR 57,-(CH 2) r(CHR 61) sCONR 58R 59,-(CH 2) r(CHR 61) sPO (OR 60) 2,-(CH 2) r(CHR 61) sSO 2R 62Or-(CH 2) r(CHR 61) sC 6H 4R 8
R 45Be H, alkyl, thiazolinyl ,-(CH 2) o(CHR 61) sOR 55,-(CH 2) o(CHR 61) sSR 56,-(CH 2) o(CHR 61) sNR 33R 34,-(CH 2) o(CHR 61) sOCONR 33R 75,-(CH 2) o(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) s(CHR 61) sCONR 58R 59,-(CH 2) s(CHR 61) sPO (OR 60) 2,-(CH 2) s(CHR 61) sSO 2R 62Or-(CH 2) s(CHR 61) sC 6H 4R 8
R 46Be H, alkyl, thiazolinyl or-(CH 2) o(CHR 61) pC 6H 4R 8
R 47Be H, alkyl, thiazolinyl or-(CH 2) o(CHR 61) sOR 55
R 48Be H, low alkyl group, low-grade alkenyl or aryl lower alkyl;
R 49Be H, alkyl, thiazolinyl ,-(CHR 61) sCOOR 57, (CHR 61) sCONR 58R 59, (CHR 61) sPO (OR 60) 2,-(CHR 61) sSOR 62Or-(CHR 61) sC 6H 4R 8
R 50Be H, low alkyl group or aryl lower alkyl;
R 51Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) pPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) p(CHR 61) sC 6H 4R 8
R 52Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) pPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) p(CHR 61) sC 6H 4R 8
R 53Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sSR 56,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 57,-(CH 2) o(CHR 61) sCONR 58R 59,-(CH 2) o(CHR 61) pPO (OR 60) 2,-(CH 2) p(CHR 61) sSO 2R 62Or-(CH 2) p(CHR 61) sC 6H 4R 8
R 54Be H, alkyl, thiazolinyl ,-(CH 2) m(CHR 61) sOR 55,-(CH 2) m(CHR 61) sNR 33R 34,-(CH 2) m(CHR 61) sOCONR 33R 75,-(CH 2) m(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) COOR 57,-(CH 2) o(CHR 61) sCONR 58R 59Or-(CH 2) o(CHR 61) sC 6H 4R 8
R 55Be H, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH 2) m(CHR 61) sOR 57,-(CH 2) m(CHR 61) sNR 34R 63,-(CH 2) m(CHR 61) sOCONR 75R 82,-(CH 2) m(CHR 61) sNR 20CONR 78R 82,-(CH 2) o(CHR 61) s-COR 64,-(CH 2) o(CHR 61) COOR 57Or-(CH 2) o(CHR 61) sCONR 58R 59
R 56Be H, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH 2) m(CHR 61) sOR 57,-(CH 2) m(CHR 61) sNR 34R 63,-(CH 2) m(CHR 61) sOCONR 75R 82,-(CH 2) m(CHR 61) sNR 20CONR 78R 82,-(CH 2) o(CHR 61) s-COR 64Or-(CH 2) o(CHR 61) sCONR 58R 59
R 57Be H, low alkyl group, low-grade alkenyl, aromatic yl elementary alkyl or heteroaryl low alkyl group;
R 58Be H, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl or heteroaryl-low alkyl group;
R 59Be H, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl or heteroaryl-low alkyl group; Perhaps
R 58And R 59Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 60Be H, low alkyl group, low-grade alkenyl, aryl or aryl lower alkyl;
R 61Be alkyl, thiazolinyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-low alkyl group ,-(CH 2) mOR 55,-(CH 2) mNR 33R 34,-(CH 2) mOCONR 75R 82,-(CH 2) mNR 20CONR 78R 82,-(CH 2) oCOOR 37,-(CH 2) oNR 58R 59Or-(CH 2) oPO (COR 60) 2
R 62Be low alkyl group, low-grade alkenyl, aryl, heteroaryl or aryl lower alkyl;
R 63Be H, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-low alkyl group ,-COR 64,-COOR 57,-CONR 58R 59,-SO 2R 62Or-PO (OR 60) 2
R 34And R 63Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 64Be H, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-low alkyl group ,-(CH 2) p(CHR 61) sOR 65,-(CH 2) p(CHR 61) sSR 66Or-(CH 2) p(CHR 61) sNR 34R 63,-(CH 2) P(CHR 61) sOCONR 75R 82,-(CH 2) P(CHR 61) sNR 20CONR 78R 82
R 65Be H, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl, heteroaryl-low alkyl group ,-COR 57,-COOR 57Or-CONR 58R 59
R 66Be H, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl, heteroaryl-low alkyl group or-CONR 58R 59
M is 2-4; O is 0-4; P is 1-4; Q is 0-2; R is 1 or 2; S is 0 or 1;
Z is the chain of 11 a-amino acid residues, the position of described amino-acid residue in described chain begins counting from-terminal amino acid, thus, according to they positions in chain, these amino-acid residues are Gly, Pro, Pro, Pro (4NHCOPhe) or have formula-A-CO-, or have formula-B-CO-, perhaps have one of following type:
C：-NR 20CH(R 72)CO-；
D：-NR 20CH(R 73)CO-；
E：-NR 20CH(R 74)CO-；
F:-NR 20CH (R 84) CO-; And
H:-NR 20-CH (CO-)-(CH 2) 4-7-CH (CO-)-NR 20-,-NR 20-CH (CO-)-(CH 2) pSS (CH 2) p-CH (CO-)-NR 20-,-NR 20-CH (CO-)-((CH 2) pNR 20CO (CH 2) p-CH (CO-)-NR 20-and-NR 20-CH (CO-)-((CH 2) pNR 20CONR 20(CH 2) p-CH (CO-)-NR 20-;
R 71Be low alkyl group, low-grade alkenyl ,-(CH 2) p(CHR 61) sOR 75,-(CH 2) p(CHR 61) sSR 75,-(CH 2) p(CHR 61) sNR 33R 34,-(CH 2) p(CHR 61) sOCONR 33R 75,-(CH 2) p(CHR 61) sNR 20CONR 33R 82,-(CH 2) o(CHR 61) sCOOR 75,-(CH 2) pCONR 58R 59,-(CH 2) pPO (OR 62) 2,-(CH 2) pSO 2R 62Or-(CH 2) o-C 6R 67R 68R 69R 70R 76
R 72Be H, low alkyl group, low-grade alkenyl ,-(CH 2) p(CHR 61) sOR 85Or-(CH 2) p(CHR 61) sSR 85
R 73Be-(CR 86R 87) oR 77,-(CH 2) rO (CH 2) oR 77,-(CH 2) rS (CH 2) oR 77Or-(CH 2) rNR 20(CH 2) oR 77
Wherein X be-O-,-NR 20-or-S-; U is 1-3, and t is 1-6;
R 75Be low alkyl group, low-grade alkenyl or aryl lower alkyl;
R 33And R 75Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 75And R 82Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 76Be H, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH 2) oOR 72,-(CH 2) oSR 72,-(CH 2) oNR 33R 34,-(CH 2) oOCONR 33R 75,-(CH 2) oNR 20CONR 33R 82,-(CH 2) oCOOR 75,-(CH 2) oCONR 58R 59,-(CH 2) oPO (OR 60) 2,-(CH 2) pSO 2R 62Or-(CH 2) oCOR 64
R 77Be-C 6R 67R 68R 69R 70R 76Or the heteroaryl of one of following formula
Figure A2005800491410018C1
Figure A2005800491410020C1
R 78Be H, low alkyl group, aryl or aryl lower alkyl;
R 78And R 82Can form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 79Be H, low alkyl group, aryl or aryl lower alkyl, perhaps
R 78And R 79Can be together :-(CH 2) 2-7-,-(CH 2) 2O (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 80Be H or low alkyl group;
R 81Be H, low alkyl group or aryl lower alkyl;
R 82Be H, low alkyl group, aryl, heteroaryl or aryl lower alkyl;
R 33And R 82Form together :-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-;
R 83Be H, low alkyl group, aryl or-NR 78R 79
R 84Be-(CH 2) m(CHR 61) sOH ,-(CR 86R 87) pOR 80,-(CR 86R 87) pCOOR 80,-(CH 2) m(CHR 61) sSH ,-(CR 86R 87) pSR 80-(CH 2) pCONR 78R 79,-(CH 2) pNR 80CONR 78R 79,-(CH 2) pC 6H 4CONR 78R 79,-(CH 2) pC 6H 4NR 80CONR 78R 79,-(CR 86R 87) oPO (OR 60) 2,-(CR 86R 87) pSO 2R 60,-(CR 86R 87) pSOR 60,-(CH 2) m(CHR 61) sOPO (OR 60) 2, or-(CH 2) m(CHR 61) sOSO 2R 60
R 85Be low alkyl group or low-grade alkenyl;
R 86Be low alkyl group or the halogen that H, H can be replaced by halogen;
R 87Be low alkyl group or the halogen that H, H can be replaced by halogen;
Condition is: in the chain of described 11 a-amino acid residue Z,
-1 to 11 amino-acid residue is:
-P1:C type or D type or E type or F type;
-P2:C type or D type or E type or F type;
-P3:C type or F type, perhaps this residue is Gly;
-P4:C type or D type or F type or E type, perhaps this residue is Gly or Pro;
-P5:E type or C type or F type, perhaps this residue is Gly or Pro;
-P6:E type or F type or E type or C type, perhaps this residue is Gly or Pro;
-P7:C type or E type or F type perhaps have formula-A-CO-, and perhaps this residue is Gly or Pro;
-P8:D type or C type or F type perhaps have formula-A-CO, and perhaps this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or E type or F type;
-P10:D type or C type or F type or E type, and
-P11:C type or D type or E type or F type, perhaps
-P2 and P10 can form the group of H type together, and
Condition is: if template is DPro LPro, the amino-acid residue of P1 to P11 position is not:
-P1：Arg
-P2: the Cys that connects P10 position Cys by disulfide linkage
-P3：Thr
-P4：Lys
-P5：Ser
-P6：Ile
-P7：Pro
-P8：Pro
-P9：Ile
-P10: by the Cys of disulfide linkage connection P10 position Cys, and
-P11：Phe。
2. according to the compound of claim 1 or 2, wherein
It is formula (a1) or (a2) or group (a3).
3. according to the compound of claim 2, wherein, A is the group of one of formula A1 to A69;
R 1Be H or low alkyl group;
R 2Be H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 3Be H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group), (CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 4Be H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 5Be low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group), (CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group), (CH 2) oN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be alkyl, thiazolinyl, aryl, aryl lower alkyl or heteroaryl-low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 6Be H, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R7 be low alkyl group, low-grade alkenyl ,-(CH 2) qOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) qSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) qNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) qOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group), (CH 2) qNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) qN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) rCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) qCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) rPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl), (CH 2) rSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl), (CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 9Be low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 10Be low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 11Be H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 3And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 12Be H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) rCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) rCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) rPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 13Be low alkyl group, low-grade alkenyl ,-(CH 2) qOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) qSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) qNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) qOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) qNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) qN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) rCOO 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) qCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) rPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) rSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 14Be H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20Be H, low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) ,-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 15Be low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75 are-(CH together 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group), (CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl), particularly advantageous NR 20CO low alkyl group (R 20=H or low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 16Be low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy); And
R 17Be low alkyl group, low-grade alkenyl ,-(CH 2) qOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) qSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) qNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) qOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) qNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) qN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) rCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) qCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) rPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) rSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
4. according to the compound of claim 3, wherein, A is formula A5 (R wherein 2Be H), A8, A22, A25, A38 (R wherein 2Be H), the group of one of A42 and A50.
5. according to the compound of claim 4, wherein, A is the group of following formula:
Figure A2005800491410033C1
Wherein, R 20Be H or low alkyl group; And R 64Be alkyl, thiazolinyl ,-[(CH 2) u-X] t-CH 3(wherein X be-O-,-NR 20Or-S-, u is 1-3, and t is 1-6), aryl, aryl lower alkyl or heteroaryl-low alkyl group.
6. according to the compound of claim 5, R wherein 64Be n-hexyl, n-heptyl, 4-(phenyl) phenmethyl, diphenyl methyl, 3-amino-propyl group, 5-amino-amyl group, methyl, ethyl, sec.-propyl, isobutyl-, n-propyl, cyclohexyl, cyclohexyl methyl, normal-butyl, phenyl, phenmethyl, (3-indyl) methyl, 2-(3-indyl) ethyl, (4-phenyl) phenyl, n-nonyl, CH 3-OCH 2CH 2-OCH 2-and CH 3-(OCH 2CH 2) 2-OCH 2-.
7. according to the compound of claim 2, wherein, A is the group of one of formula A70 to A104:
R 20Be H or low alkyl group;
R 18It is low alkyl group;
R 19Be low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) pSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl, R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) pCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) pCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H or low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) pSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) oC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 21Be H, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl), (CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or (CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 22Be low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF, low alkyl group, low-grade alkenyl or lower alkoxy);
R 23Be H, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-, R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl), particularly advantageous NR 20CO low alkyl group (R 20=H or low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 24Be low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl), particularly advantageous NR 20CO low alkyl group (R 20=H or low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 25Be H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 26Be H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps, R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy); Perhaps, alternately, R 25And R 26Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 34(CH 2) 2-;
R 27Be H, low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl, R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy);
R 28Be low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59:-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy); And
R 29Be low alkyl group, low-grade alkenyl ,-(CH 2) oOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSR 56(R wherein 56Be low alkyl group or low-grade alkenyl) ,-(CH 2) oNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl), particularly advantageous NR 20CO low alkyl group (R 20=H or low alkyl group) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
8. according to the compound of claim 7, R wherein 23, R 24And R 29Be-NR 20-CO-low alkyl group, wherein R 20Be H or low alkyl group.
9. according to the compound of claim 7 or 8, wherein A is formula A74 (R wherein 22Be H), A75, A76, A77 (R wherein 22Be H), the group of one of A78 and A79.
10. according to compound any in the claim 2 to 9, wherein, B is formula-NR 20CH (R 71)-group or group A5 (R wherein 22Be H), A8, A22, A25, A38 (R wherein 2Be H), the enantiomer of one of A42, A47 and A50.
11. according to the compound of claim 10, wherein B-CO is Ala, Arg, Asn, Cys, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Pro (5RPhe), Ser, Thr, Trp, Tyr, Val, Cit, Orn, tBuA, Sar, t-BuG, 4AmPhe, 3AmPhe, 2AmPhe, Phe (mC (NH 2)=NH, Phe (pC (NH 2)=NH, Phe (mNHC (NH 2)=NH, Phe (pNHC (NH 2)=NH, Phg, Cha, C 4Al, C 5Al, Nle, 2-Nal, 1-Nal, 4Cl-Phe, 3Cl-Phe, 2Cl-Phe, 3,4Cl 2Phe, 4F-Phe, 3F-Phe, 2F-Phe, Tic, Thi, Tza, Mso, AcLys, Dpr, A 2Bu, Dbu, Abu, Aha, Aib, Y (Bzl), Bip, S (Bzl), T (Bzl), hCha, hCys, hSer, hArg, hPhe, Bpa, Pip, OctG, MePhe, MeNle, MeAla, MeIle, MeVal or MeLeu.
12. according to the compound of claim 10, wherein, B is the following formula group with (L)-configuration
Figure A2005800491410041C1
R wherein 20Be H or low alkyl group; And R 64It is alkyl; Thiazolinyl;-[(CH 2) u-X] t-CH 3, wherein X be-O-,-NR 20-or-S-, u is that 1-3 and t are 1-6; Aryl; Aryl lower alkyl or heteroaryl-low alkyl group.
13. according to the compound of claim 12, wherein R 64Be n-hexyl, n-heptyl, 4-(phenyl) phenmethyl, diphenyl methyl, 3-amino-propyl group, 5-amino-amyl group, methyl, ethyl, sec.-propyl, isobutyl-, n-propyl, cyclohexyl, cyclohexyl methyl, normal-butyl, phenyl, phenmethyl, (3-indyl) methyl, 2-(3-indyl) ethyl, (4-phenyl) phenyl, n-nonyl, CH 3-OCH 2CH 2-OCH 2-or CH 3-(OCH 2CH 2) 2-OCH 2-.
14. according to the compound of claim 1, wherein
Figure A2005800491410041C2
It is the group of formula (b1) or (1);
R 1Be H or low alkyl group;
R 20Be H or low alkyl group;
R 30Be H or methyl;
R 31Be H, low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(wherein: R 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl), (CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) rC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy); Most preferably-CH 2CONR 58R 59(R 58Be H or low alkyl group; And R 59Be low alkyl group or low-grade alkenyl);
R 32Be H or methyl;
R 33Be low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 34R 63(R wherein 34Be low alkyl group or low-grade alkenyl; R 63Be H or low alkyl group; Perhaps R 34And R 63Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group), (CH 2) mOCONR 75R 82(R wherein 75Be low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 75And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 78R 82(R wherein 20Be H or low alkyl group; R 78Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 78And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group);
R 34Be H or low alkyl group;
R 35Be H, low alkyl group, low-grade alkenyl ,-(CH 2) mOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) mNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) mN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group);
R 36Be low alkyl group, low-grade alkenyl or aryl lower alkyl;
R 37Be H, low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy); And
R 38Be H, low alkyl group, low-grade alkenyl ,-(CH 2) pOR 55(R wherein 55Be low alkyl group or low-grade alkenyl) ,-(CH 2) pNR 33R 34(R wherein 33Be low alkyl group or low-grade alkenyl; R 34Be H or low alkyl group; Perhaps R 33And R 34Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pOCONR 33R 75(R wherein 33Be H or low alkyl group or low-grade alkenyl; R 75It is low alkyl group; Perhaps R 33And R 75Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pNR 20CONR 33R 82(R wherein 20Be H or low alkyl group; R 33Be H or low alkyl group or low-grade alkenyl; R 82Be H or low alkyl group; Perhaps R 33And R 82Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) pN (R 20) COR 64(R wherein 20Be H or low alkyl group; R 64Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCOOR 57(R wherein 57Be low alkyl group or low-grade alkenyl) ,-(CH 2) oCONR 58R 59(R wherein 58Be low alkyl group or low-grade alkenyl; And R 59Be H, low alkyl group; Perhaps R 58And R 59Be together-(CH 2) 2-6-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-or-(CH 2) 2NR 57(CH 2) 2-; R wherein 57Be H or low alkyl group) ,-(CH 2) oPO (OR 60) 2(R wherein 60Be low alkyl group or low-grade alkenyl) ,-(CH 2) oSO 2R 62(R wherein 62Be low alkyl group or low-grade alkenyl) or-(CH 2) qC 6H 4R 8(R wherein 8Be H, F, Cl, CF 3, low alkyl group, low-grade alkenyl or lower alkoxy).
15. according to the compound of claim 14, wherein, R 1Be H; R 20Be H; R 30Be H; R 31Be carboxymethyl or lower alkoxycarbonyl methyl; R 32Be H; R 35It is methyl; R 36It is methoxyl group; R 37Be H and R 38Be H.
16. according to compound any in the claim 1 to 15, wherein 1 to 11 a-amino acid residue is in the Z chain:
-P1:C type or D type or E type or F type;
-P2:E type or F type or C type;
-P3:C type or F type, perhaps this residue is Gly;
-P4:C type or E type or F type, perhaps this residue is Gly or Pro;
-P5:E type or F type, perhaps this residue is Gly or Pro;
-P6:C type or D type or F type, perhaps this residue is Gly or Pro;
-P7:F type or have formula-A-CO-, perhaps this residue is Gly or Pro;
-P8:D type or C type or have formula-A-CO, perhaps this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or E type or F type;
-P10:F type or C type or E type:
-P11:E type or F type or C type or D type; Perhaps
-P2 and P10 form the group of H type together;
Condition is: if template is DPro- LPro, the amino-acid residue of P1 to P11 position is not so:
- P1： Arg
-P2: the Cys that links to each other with the Cys of P10 position by disulfide linkage
- P3： Thr
- P4 Lys
- P5 Ser
- P6 Ile
- P7 Pro
- P8 Pro
- P9 Ile
The Cys that-P10 links to each other with the Cys of P10 position by disulfide linkage; And
- P11 Phe。
17. according to the compound of claim 16, wherein 1 to 11 a-amino acid residue is in the Z chain:
-P1:Nle, Ile, Aoc, hLeu, Chg, OctG, hPhe, 4AmPhe, Ch a, Phe, Tyr, 2Cl-Phe, Trp, 1-Nal, Leu, Cha or Arg;
-P2:Cys, Glu, Nle, Thr or Gln;
-P3:Thr, Ala or Abu;
-P4:Lys, Nle, Ala, Abu or Thr;
-P5:Ser, AlloThr or Dpr;
-P6:Ile, c5al, Leu, Nle, Aoc, OctG, Cha, hLeu, hPhe, Chg, t-BuA, Glu or Asp;
- P7： Pro；
-P8:Pro, Ala or Pro (4NHCOPhe);
-P9:Tyr, Phe, Ile, Nle, Cha, Gln, Arg, Lys, His, Thr or Ala;
-P10:Cys, Arg, Nle, Gln, Lys, Met, Thr or Ser;
-P11:Tyr, Gln, Arg, Ser, Nle, 2-Nal, 2Cl-Phe, Cha, Phg, Tyr, Phe, Asp, Asn or Thr; And
-Cys, if exist at P2 and P10, it can form disulfide linkage.
18. according to compound any in the claim 1 to 15, wherein 1 to 11 a-amino acid residue is in the Z chain:
-P1:C type or D type or E type;
-P2:F type or C type;
-P3:F type;
-P4:C type or E type;
-P5:E type or F type;
-P6:F type;
-P7:F type or have formula-A-CO-, perhaps this residue is Gly or Pro;
-P8:C type or have formula-A-CO-, perhaps this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or F type;
-P10:F type or C type or E type;
-P11:E type or D type or F type; Perhaps
-P2 and P10 form the group of H type together.
19. according to the compound of claim 18, wherein 1 to 11 a-amino acid residue is:
-P1:Phe, hPhe, 4AmPhe, Nle, Chg, Ile, Tyr, Arg, Trp, 2Cl-Phe, Arg, 1-Nal or Cha;
-P2:Cys, Glu or Nle;
- P3： Thr；
-P4:Lys or Nle;
-P5:Ser, AlloThr or Dpr;
-P6:Asp or Glu;
- P7： Pro；
- P8： Pro；
-P9:Ile, Nle, Cha, Gln, Tyr or Ala;
-P10:Cys, Arg or Nle;
-P11:Thr, Asp, Ser, Tyr, Phe, Asn or Arg; And
-Cys, if exist at P2 and P10, it can form disulfide linkage.
20. according to compound any in the claim 1 to 15, wherein 1 to 11 a-amino acid residue is in the Z chain:
-P1:C type or D type;
-P2:F type;
-P3:F type or C type;
-P4:C type or F type;
-P5:F type;
-P6:C type;
-P7: have formula-A-CO-, perhaps this residue is Gly or Pro;
-P8: have formula-A-CO-, perhaps this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:D type or F type or C type;
-P10:F type or C type or E type;
-P11:E type or F type or D type; Perhaps
-P2 and P10 form the group of H type together.
21. according to the compound of claim 20, wherein 1 to 11 a-amino acid residue is:
-P1:Ile, Nle, Aoc, hLeu, Chg, OctG or hPhe;
-P2:Cys, Glu, Thr or Gln;
-P3:Thr, Ala or Abu;
-P4:Ala, Thr or Abu;
- P5： Ser；
-P6:OctG, Ile, Cha, Leu, c5al, Nle, Aoc, Chg, tBuA or hLeu;
- P7： Pro；
-P8:Pro or Pro (4NHCOPhe);
-P9:Gln, Tyr, ILe or Phe;
-P10:Cys, Lys, Gln, Thr, Met or Arg;
-P11:Tyr, Ser, Arg, Gln, Nle, 2-Nal, 2Cl-Phe, Phe, Cha or Phg; And
-Cys, if exist at P2 and P10, it can form disulfide linkage.
22. according to compound any in the claim 1 to 15, wherein 1 to 11 a-amino acid residue is in the Z chain:
-P1:C type or D type or E type;
-P2:F type;
-P3:F type;
-P4:E type;
-P5:F type;
-P6:C type or D type;
-P7:F type or have formula-A-CO-, perhaps this residue is Gly or Pro;
-P8:C type or have formula-A-CO-, perhaps this residue is Gly or Pro;
-P9:C type or E type or F type;
-P10:F type;
-P11:E type or D type; Perhaps
-P2 and P10 form the group of H type together;
Condition is: if template is DPro- LPro, the amino-acid residue of P1 to P11 position is not so:
- P1： Arg
-P2: the Cys that links to each other with the Cys of P10 position by disulfide linkage
- P3： Thr
- P4 Lys
- P5 Ser
- P6 Ile
- P7 Pro
- P8 Pro
- P9 Ile
The Cys that-P10 links to each other with the Cys of P10 position by disulfide linkage; And
- P11 Phe。
23. according to the compound of claim 22, wherein 1 of the Z chain to 11 a-amino acid residue is:
-P1:Cha, Tyr or Trp
- P2： Cys
- P3： Thr
- P4： Lys
- P5： Ser
- P6： Leu
- P7： Pro
- P8： Pro
- P9： Lys
- P10： Cys
-P11:Arg; And
The Cys residue that P2 and P10 position exist can form disulfide linkage.
24. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Phe；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Asp；
- P7： Pro；
- P8： Pro；
- P9： Ile；
- P10： Cys；
- P11： Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
25. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Ile；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Asp；
- P7： Pro；
- P8： Pro；
- P9： Nle；
- P10： Cys；
- P11： Arg；
The Cys of P2 and P10 position forms disulfide linkage.
26. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Ile；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Asp；
- P7： Pro；
- P8： Pro；
- P9： Cha；
- P10： Cys；
- P11： Arg；
The Cys of P2 and P10 position forms disulfide linkage.
27. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Ile；
- P2： Cys；
- P3： Thr；
- P4： Nle；
- P5： Ser；
- P6： Asp；
- P7： Pro；
- P8： Pro；
- P9： Ile；
- P10： Cys；
- P11： Arg
The Cys of P2 and P10 position forms disulfide linkage.
28. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Phe；
- P2： Cys；
- P3： Thr；
- P4： Nle；
- P5： Ser；
- P6： Asp；
- P7： Pro；
- P8： Pro；
- P9： Ile；
- P10： Cys；
- P11： Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
29. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Chg；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Asp；
- P7： Pro；
- P8： Pro；
- P9： Ile；
- P10： Cys；
- P11： Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
30. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Arg；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Asp；
- P7： Pro；
- P8： Pro；
- P9： Ile；
- P10： Cys；
- P11： Phe；
The Cys of P2 and P10 position forms disulfide linkage.
31. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Nle；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Ile；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Gln；
The Cys of P2 and P10 position forms disulfide linkage.
32. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Nle；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Ile；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
33. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： hPhe；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： OctG；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Gln
The Cys of P2 and P10 position forms disulfide linkage.
34. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： OctG；
- P2： Gln；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Ile；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Thr；
- P11： Tyr。
35. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： hPhe；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Cha；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Phe；
The Cys of P2 and P10 position forms disulfide linkage.
36. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： OctG；
- P2： Glu；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Ile；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Lys；
- P11： Tyr。
37. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： OctG；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Cha；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Phe；
The Cys of P2 and P10 position forms disulfide linkage.
38. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： hPhe；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Cha；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Gln；
The Cys of P2 and P10 position forms disulfide linkage.
39. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： OctG；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Cha；
- P7： Pro；
- P8： Pro(4NHCOPhe)；
- P9： Gln；
- P10： Cys；
- P11： Gln；
The Cys of P2 and P10 position forms disulfide linkage.
40. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： hPhe；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： OctG；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
41. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Chg；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Asp；
- P7： Pro；
- P8： Pro；
- P9： Ile；
- P10： Cys；
- P11： Thr；
The Cys of P2 and P10 position forms disulfide linkage.
42. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Chg；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Asp；
- P7： Pro；
- P8： Pro；
- P9： Ile；
- P10： Cys；
- P11： Asp；
The Cys of P2 and P10 position forms disulfide linkage.
43. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： OctG；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Cha；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Gln；
The Cys of P2 and P10 position forms disulfide linkage.
44. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： OctG；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： Ile；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
45. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： OctG；
- P2： Cys；
- P3： Thr；
- P4： Ala；
- P5： Ser；
- P6： OctG；
- P7： Pro；
- P8： Pro；
- P9： Gln；
- P10： Cys；
- P11： Gln；
The Cys of P2 and P10 position forms disulfide linkage.
46. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Cha；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Leu；
- P7： Pro；
- P8： Pro；
- P9： Lys；
- P10： Cys；
- P11： Arg；
The Cys of P2 and P10 position forms disulfide linkage.
47. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Tyr；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Leu；
- P7： Pro；
- P8： Pro；
- P9： Lys；
- P10： Cys；
- P11： Arg；
The Cys of P2 and P10 position forms disulfide linkage.
48. formula I compound according to claim 1, wherein, described template is DPro- LPro, and 1 to 11 amino-acid residue is:
- P1： Trp；
- P2： Cys；
- P3： Thr；
- P4： Lys；
- P5： Ser；
- P6： Leu；
- P7： Pro；
- P8： Pro；
- P9： Lys；
- P10： Cys；
- P11： Arg；
The Cys of P2 and P10 position forms disulfide linkage.
49. enantiomer according to the formula I compound of claim 1 definition.
50. any one compound in the claim 1 to 49, it is used as the treatment effective substance.
51. compound according to claim 50, it has the selectivity protease inhibiting activity, particularly at inhibition activity and/or antitumour activity and/or anti-inflammatory activity and/or anti-infection activity and/or anti-cardiac vascular activity and/or the anti-immunocompetence and/or the anti-neurodegeneration activity of cathepsin G or elastoser or tryptase.
52. pharmaceutical composition wherein contains compound any in the with good grounds claim 1 to 49 and pharmaceutical inert carriers.
53. according to the described composition of claim 52, it is and is suitable for per os, part, transdermal, uses through cheek, saturating mucous membrane or through lung, perhaps is adapted to pass through injection or sucks the form of using.
54. according to the compound of claim 52 or 53, it is the form of tablet, drageeing, capsule, solution, liquid, gelifying agent, plaster, creme, ointment, syrup, slurry, suspension, spraying, atomizer or suppository.
55. be used to prepare the purposes of the medicine that is used as proteinase inhibitor according to compound any in the claim 1 to 49.
56. according to the described purposes of claim 55, wherein, described proteolytic enzyme suppresses medicine and is used to prevent infection in the healthy individual, infected patient's infection perhaps is used for slowing down, perhaps be used for the protease activity mediation or cause cancer, perhaps be used for the protease activity mediation or cause Immunological diseases, perhaps be used for the protease activity mediation or cause inflammation, perhaps be used for the protease activity mediation or cause immunoreactive situation.
57. according to claim 18,19 and 24-30 in any one compound be used to prepare the purposes of the medicine of the inhibitor that is used as cathepsin G.
58. according to claim 20,21 and 31-42 in any one compound be used to prepare the purposes of the medicine of the inhibitor that is used as elastoser.
59. according to claim 22,23 and 43-45 in any one compound be used to prepare the purposes of the medicine of the inhibitor that is used as tryptase.
60. the method for any one compound among the production claim 1-48, this method comprises:
(a) will be by 5,6 or 7 the derivative coupling of the suitable N-protected of amino acid whose warp in suitably functionalized solid support and the end product of wanting, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(b) remove the N-protected group from thus obtained product;
(c) with in thus obtained product and the end product wanted again near the derivative coupling of the suitable N-protected of that amino acid whose warp of one of-terminal amino acid residue, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(d) remove the N-protected group from thus obtained product;
(e) repeating step (c) and (d) has been introduced the-terminal amino acid residue up to;
(f) with the compound coupling of thus obtained product and following general formula
Figure A2005800491410065C1
Wherein
Figure A2005800491410065C2
Have defined implication in the claim 1, and X is the N-protected group, perhaps, if
Figure A2005800491410065C3
Be defined in the claim 1 (a1) or (a2),
(fa) with the product of acquisition in the step (e) and the derivative coupling of the suitable N-protected of the amino acid whose warp of following general formula, described general formula is:
HOOC-B-H III or HOOC-A-H IV
Wherein, B and A have defined implication in the claim 1, and any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(fb) remove the N-protected group from thus obtained product; And
(fc) with thus obtained product and the derivative coupling that is respectively the suitable N-protected of amino acid whose warp of above-mentioned general formula I V and III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care; And, respectively, if
Figure A2005800491410066C1
Be the group (a3) of definition in the claim 1,
(fa ') with the derivative coupling of the suitable N-protected of amino acid whose warp of middle product that obtains of step (e) and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(fb ') removes the N-protected group from thus obtained product; And
(fc ') with the derivative coupling of the suitable N-protected of amino acid whose warp of thus obtained product and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(g) remove the N-protected group from step (f) or the product that obtains (fc) or (fc ');
(h) with thus obtained product and the 11st the derivative coupling of the suitable N-protected of amino acid whose warp in the end product of wanting, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(i) remove the N-protected group from thus obtained product;
(j) with in thus obtained product and the end product wanted from the derivative coupling of the 11st the suitable N-protected of that amino acid whose warp far away again, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(k) remove the N-protected group from thus obtained product;
(l) repeating step (j) and (k) is up to having introduced all amino-acid residues;
(m) if necessary, the one or more shielded functional group selectivity that exists in the molecule is gone protection, and the reaction active groups that discharges is thus suitably replaced;
(n) if necessary, between the side chain of the 2nd and 10 s' suitable amino-acid residue, form the interchain key;
(o) thus obtained product and solid support are broken away from;
(p) will be from cracked product cyclisation on the solid support;
(q) remove any blocking group that exists in any member's the functional group of amino-acid residue chain, and, if necessary, remove other any blocking group that may exist in the molecule; And
(r) if necessary, thus obtained product is converted into pharmacy acceptable salt, perhaps thus obtained pharmacy acceptable salt or unacceptable salt are converted into corresponding formula I free cpds, perhaps are converted into different, pharmacy acceptable salt.
61. the method for any one compound among the production claim 1-48, this method comprises:
(a ') will be through the suitably functionalized solid support and the compound coupling of following general formula
Figure A2005800491410067C1
Wherein
Figure A2005800491410067C2
Have defined implication in the claim 1, and X is the N-protected group, if perhaps
Figure A2005800491410068C1
Be the group (a1) or (a2) of definition in the claim 1,
(solid support that a ' a) is suitably functionalized with described warp and the derivative coupling of the suitable N-protected of the amino acid whose warp of following general formula,
HOOC-B-H III or HOOC-A-H IV
Wherein, B and A have defined implication in the claim 1, and any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(a ' b) remove the N-protected group from thus obtained product; And
(a ' c) with thus obtained product and the derivative coupling that is respectively the suitable N-protected of amino acid whose warp of above-mentioned general formula I V and III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care; And, respectively, if
Be defined group (a3) in the claim 1,
The derivative coupling of the solid support that (a ' a ') is suitably functionalized with described warp and the suitable N-protected of amino acid whose warp of above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(a ' b ') removes the N-protected group from thus obtained product; And
(a ' c ') with the derivative coupling of the suitable N-protected of amino acid whose warp of thus obtained product and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(b ') from step (a '), (a ' c) or the product that obtains (a ' c ') are removed the N-protected group;
(c ') with thus obtained product and the 11st the derivative coupling of the suitable N-protected of amino acid whose warp in the end product of wanting, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(d ') removes the N-protected group from thus obtained product;
(e ') with in thus obtained product and the end product wanted from the derivative coupling of the 11st the suitable N-protected of that amino acid whose warp far away again, any functional group that can exist in the amino acid derivative of described N-protected is equally by due care;
(f ') removes the N-protected group from thus obtained product;
(g ') repeating step (e ') and (f ') are up to having introduced all amino-acid residues;
(h ') goes protection to the one or more shielded functional group selectivity that exists in the molecule if necessary, and the reaction active groups that discharges is thus suitably replaced;
(i ') forms the interchain key if necessary between the side chain of the 2nd and 10 s' suitable amino-acid residue;
(j ') breaks away from thus obtained product and solid support;
(k ') will be from cracked product cyclisation on the solid support;
(l ') removes any blocking group that exists in any member's the functional group of amino-acid residue chain, and, if necessary, remove other any blocking group that may exist in the molecule; And
(m ') if necessary, thus obtained product is converted into its pharmacy acceptable salt, perhaps thus obtained pharmacy acceptable salt or unacceptable salt are converted into corresponding formula I free cpds, perhaps are converted into different, pharmacy acceptable salt.
62. the improvement according to the method for claim 60 or 61 is used to produce the compound according to claim 49, wherein, uses the enantiomer of all chiral raw material.
CNA2005800491411A 2005-02-17 2005-02-17 Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity Pending CN101142228A (en)

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CN106029689A (en) * 2013-12-27 2016-10-12 波利弗尔股份公司 Beta-hairpin peptidomimetics as selective elastase inhibitors
CN109195580A (en) * 2016-05-31 2019-01-11 波利弗尔股份公司 β-hairpin peptidomimetics and its Aerosol dosage form with elastase inhibitory activity

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KR101420198B1 (en) * 2005-02-17 2014-08-13 폴리포 리미티드 Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity
WO2007079597A1 (en) 2006-01-16 2007-07-19 Polyphor Ltd. Template - fixed peptidomimetics with antimicrobial activity
US8633163B2 (en) 2007-01-29 2014-01-21 Polyphor Ltd. Template-fixed peptidomimetics
PT2132221E (en) 2007-02-28 2010-10-26 Univ Zuerich Template-fixed peptidomimetics
US20110230426A1 (en) * 2008-08-08 2011-09-22 Polyphor Ag Template-fixed peptidomimetics
CN105873939B (en) * 2013-12-27 2021-08-27 波利弗尔股份公司 Beta-hairpin peptidomimetics as selective elastase inhibitors
US20170319643A1 (en) 2016-05-05 2017-11-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Serv Lipoprotein targeting protease inhibitors and uses
JPWO2022202816A1 (en) * 2021-03-22 2022-09-29

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CN106029689A (en) * 2013-12-27 2016-10-12 波利弗尔股份公司 Beta-hairpin peptidomimetics as selective elastase inhibitors
CN106029689B (en) * 2013-12-27 2021-09-28 波利弗尔股份公司 Beta-hairpin peptidomimetics as selective elastase inhibitors
CN109195580A (en) * 2016-05-31 2019-01-11 波利弗尔股份公司 β-hairpin peptidomimetics and its Aerosol dosage form with elastase inhibitory activity
CN109310613A (en) * 2016-05-31 2019-02-05 波利弗尔股份公司 β-hairpin peptidomimetics and its Aerosol dosage form with elastase inhibitory activity

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KR101272633B1 (en) 2013-06-10
JP2008531485A (en) 2008-08-14

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